Antisense modulation of SMRT expression

ABSTRACT

Antisense compounds, compositions and methods are provided for modulating the expression of SMRT. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding SMRT. Methods of using these compounds for modulation of SMRT expression and for treatment of diseases associated with expression of SMRT are provided.

FIELD OF THE INVENTION

[0001] The present invention provides compositions and methods for modulating the expression of SMRT. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding SMRT. Such compounds have been shown to modulate the expression of SMRT.

BACKGROUND OF THE INVENTION

[0002] Steroids, retinoids, thyroid hormones, and vitamin D play critical roles in the regulation of reproduction, development, metabolism, and homeostasis. The intracellular receptors for these hormones and lipophilic compounds comprise a large family of transcription factors that regulate ligand-dependent expression of target genes. This family can be divided into two classes: the steroid receptors are normally inactive and associated with heat shock proteins in the absence of hormone, and the nuclear hormone receptors, which bind DNA and repress transcription in the absence of ligand and activate transcription upon ligand treatment. By activating or repressing target genes, the steroid/nuclear hormone receptors elicit a broad range of cellular responses, such as differentiation, proliferation, and cell death (Chen and Li, Crit. Rev. Eukaryot. Gene Expr., 1998, 8, 169-190).

[0003] The highly ordered chromatin structure of chromosomal DNA within the nuclei of eukaryotic cells presents a physical obstacle for gene transcription, by limiting access of transcription factors and RNA polymerase II core machinery to DNA templates. Posttranslational modifications such as phosphorylation, acetylation, ADP-ribosylation, and ubiquitination can reversibly modify histone proteins within chromatin, and these histone modifications affect structural alterations in local chromatin architecture during transcription. The dynamic state of histone acetylation is tightly regulated and maintained by histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzyme activities. Histone modification plays a pivotal role in controlling access of transcriptional activators, repressors, and the basal transcription machinery to regulatory sequences in the underlying DNA template to positively or negatively affect the rate of gene transcription. Hyperacetylation of core histones in gene promoters results in decondensation of chromatin, increases accessibility of transcription factors, and is correlated with gene activation. Conversely, hypoacetylation is thought to reestablish the condensed chromatin structure, favoring transcriptional repression and gene silencing (Chen and Li, Crit. Rev. Eukaryot. Gene Expr., 1998, 8, 169-190; Xu et al., Curr. Opin. Genet. Dev., 1999, 9, 140-147).

[0004] Repression of basal transcription by nuclear hormone receptors such as thyroid receptor (TR) and retinoic acid receptor (RAR) plays a critical role in oncogenesis and cellular differentiation. Several cofactors of nuclear receptors have been identified as important components of transcriptional regulation, and these coactivators and corepressors have been found to harbor intrinsic HAT and HDAC activities, respectively. The nuclear receptor corepressors, N-COR and SMRT, interact with several unliganded nuclear receptors and recruit multisubunit protein complexes containing HDACs and several other proteins. Furthermore, recent studies of RAR and TR nuclear hormone receptors have revealed that, upon ligand binding, a HDAC-containing complex is displaced from the nuclear receptor in exchange for binding of a HAT-containing complex to promoters of target genes. Thus, ligand-dependent recruitment of chromatin-remodeling activities, in the form of histone acetylation and deacetylation enzyme complexes, is believed to serve as a general mechanism underlying the switch of nuclear receptors from a transcriptionally repressed to a transcriptionally active state (Xu et al., Curr. Opin. Genet. Dev., 1999, 9, 140-147).

[0005] Nuclear hormone corepressor proteins have been demonstrated to associate with mSin3 and HDAC-containing complexes, presumably to induce chromatin condensation and in doing so, these corepressors modulate transcriptional activation or silencing of a wide variety of gene targets involved in development, differentiation, and cellular proliferation (Lee et al., J. Biol. Chem., 2000, 275, 12470-12474; Li et al., Embo J., 2000, 19, 4342-4350; Wu et al., J. Biol. Chem., 2001, 276, 24177-24185).

[0006] SMRT (also known as silencing mediator for retinoid and thyroid hormone action, Nuclear receptor co-repressor 2, NCoR2, TRAC-1, CTG26, TNRC14, and SMRTe) was originally identified and cloned from a human B-cell cDNA library as a RAR-interacting protein in a two-hybrid screen (Chen and Evans, Nature, 1995, 377, 454-457). RAR and TR directly interact with SMRT, and these protein-protein interactions bring the receptors to target promoters in the nucleus, resulting in gene repression. Ligand binding to the receptors causes dissociation of SMRT from them, resulting in ligand-dependent activation of target genes (Chen and Evans, Nature, 1995, 377, 454-457). In an accompanying paper, nuclear receptor corepressor (N-CoR) was identified and found to be related to SMRT; thus, the name TRAC was proposed for a newly identified family of thyroid-hormone- and retinoic-acid-receptor-associated corepressor proteins (Horlein et al., Nature, 1995, 377, 397-404).

[0007] The original isolate of SMRT showed significant homology to N-COR, but was substantially shorter in length. A longer isoform was later isolated and named SMRT, as it was predicted to be the major form in vivo, and the shorter, original isolate was renamed s-SMRT (Ordentlich et al., Proc. Natl. Acad. Sci. U.S.A., 1999, 96, 2639-2644). Concurrently, a second group independently identified the human and mouse SMRT-extended (SMRTe) isoforms, which included 1000 amino acids at the N-terminus bearing striking similarity to N-CoR, and found that SMRTe expression was cell-cycle regulated and transcripts were present in many mouse embryonic tissues (Park et al., Proc. Natl. Acad. Sci. U.S.A., 1999, 96, 3519-3524). Furthermore, a polyclonal antibody has been generated against SMRT and used to study its cell cycle dependent localization. SMRT is ubiquitously expressed in the nuclei of all interphase cells, and is found to be dispersed in the cytoplasm and excluded from the metaphase chromosomes in mitotic cells (Chen et al., Proc. Natl. Acad. Sci. U.S.A., 1996, 93, 7567-7571). The relative levels of SMRT expression also vary with tissue type and upon hormone treatment (Misiti et al., Endocrinology, 1998, 139, 2493-2500).

[0008] Posttranslational modification of SMRT may alter its subcellular localization and its ability to interact with nuclear hormone receptors. SMRT is a substrate for phosphorylation by multiple components of the mitogen-activated protein kinase (MAPK) cascade that operates downstream of the epidermal growth factor (EGF) receptor, and this phosphorylation appears to inhibit the ability of SMRT to bind to nuclear receptors, and correlates with a relocalization from the nucleus to the cytoplasm (Hong and Privalsky, Mol. Cell. Biol., 2000, 20, 6612-6625).

[0009] Nuclear receptors inhibit synthesis of matrix metalloproteinase-1 (MMP-1), an enzyme that degrades interstitial collagens and contributes to the pathology in numerous disorders, including the joint erosion observed in rheumatoid arthritis. Primary synovial fibroblasts express SMRT, and overexpression of SMRT was found to inhibit MMP-1 promoter activity, suggesting that SMRT maintains a repressive state of the MMP-1 gene and strictly controls regulation of interstitial collagenase (Schroen et al., Biochem. Biophys. Res. Commun., 1997, 237, 52-58).

[0010] In addition to its role in inflammation, SMRT plays a role in several cancers. The MCF-7 breast cancer cell line expresses the aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (Arnt), and SMRT physically as well as functionally interacts with these proteins, suggesting that nuclear receptor corepressors can modulate aryl hydrocarbon responsiveness in breast cancer cells (Nguyen et al., Arch. Biochem. Biophys., 1999, 367, 250-257).

[0011] Mutations in members of the nuclear receptor superfamily frequently result in neoplastic and endocrine disorders. The genetic disease characterized by resistance to thyroid hormone (RTH) exemplifies such a disorder. RTH is attributed to mutations in the TRβ allele of the thyroid hormone receptor. These mutations act in a dominant negative manner, interfering with receptor function and displaying an aberrant association with SMRT, in which ligand treatment no longer results in dissociation of SMRT from the receptor (Matsushita et al., J. Endocrinol., 2000, 167, 493-503).

[0012] SMRT is also involved in human acute promyelocytic leukemia (APL), in which the majority of patients harbor a specific gene translocation involving the RARα allele. At least five different fusion partners of RARα have been identified, but the two best-studied fusion proteins, PML-RARα and PLZF-RARα retain a wild-type affinity for retinoic acid (RA), and are able to bind to promoters of retinoic acid responsive genes. The PML-RARα and PLZF-RARα fusions have increased affinity for the corepressor SMRT, and the dissociation of SMRT from RAR normally induced by RA no longer occurs, leading to aberrant expression of target genes. Thus, PML-RARα and PLZF-RARα are leukemogenic at physiological concentrations of RA (Lin and Evans, Mol. Cell., 2000, 5, 821-830).

[0013] The pharmacological modulation of the activity and/or expression components of SMRT corepressor-containing complexes is believed to be an appropriate point of therapeutic intervention in pathological conditions such as inflammatory or autoimmune diseases, rheumatoid arthritis, resistance to thyroid hormone and other metabolic diseases, and cancers such as acute promyelocytic leukemia.

[0014] Disclosed and claimed in Wo 00/53734 are nucleic acids encoding SMRT, allelic variants of SMRT, nucleic acids with 90% homology to SMRT or which can hybridize to SMRT, as well as BAC, PAC, and cosmid clones comprising genomic or cDNA sequences encoding SMRT, DNA constructs and expression cassettes bearing suitable regulatory sequences for expression of SMRT as a biologically active protein, antisense targeted to the SMRT gene, and antibodies against the SMRT protein. Further claimed are host cells containing said nucleic acid molecules and methods for producing polypeptides encoded by SMRT, or fragments thereof, as well as the use of the DNA or polypeptide sequences of SMRT as tools to identify potential drugs for the treatment of angiogenic diseases, rheumatoid arthritis, psoriasis, eye diseases such as diabetic retinopathy and neovascular glaucoma, kidney diseases such as glomerulonephritis and diabetic nephropathy (Thierauch et al., 2000).

[0015] Currently, there are no known therapeutic agents which effectively inhibit the synthesis of SMRT and investigative strategies aimed at studying SMRT function have involved the use of antibodies for cellular localization studies (Chen et al., Proc. Natl. Acad. Sci. U.S.A., 1996, 93, 7567-7571).

[0016] Consequently, there exists a long felt need to identify methods of modulating transcriptional repression complexes and specifically for agents capable of effectively modulating SMRT function.

[0017] Antisense technology is emerging as an effective means for reducing the expression of specific gene products and may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the modulation of SMRT expression.

[0018] The present invention provides compositions and methods for modulating SMRT expression, including modulation of the extended isoform of SMRT, known as SMRTe.

SUMMARY OF THE INVENTION

[0019] The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding SMRT, and which modulate the expression of SMRT. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of SMRT in cells or tissues comprising contacting said cells or tissues with one or more of the antisense compounds or compositions of the invention. Further provided are methods of treating an animal, particularly a human, suspected of having or being prone to a disease or condition associated with expression of SMRT by administering a therapeutically or prophylactically effective amount of one or more of the antisense compounds or compositions of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention employs oligomeric compounds, particularly antisense oligonucleotides, for use in modulating the function of nucleic acid molecules encoding SMRT, ultimately modulating the amount of SMRT produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding SMRT. As used herein, the terms “target nucleic acid” and “nucleic acid encoding SMRT” encompass DNA encoding SMRT, RNA (including pre-mRNA and mRNA) transcribed from such DNA, and also cDNA derived from such RNA. The specific hybridization of an oligomeric compound with its target nucleic acid interferes with the normal function of the nucleic acid. This modulation of function of a target nucleic acid by compounds which specifically hybridize to it is generally referred to as “antisense”. The functions of DNA to be interfered with include replication and transcription. The functions of RNA to be interfered with include all vital functions such as, for example, translocation of the RNA to the site of protein translation, translocation of the RNA to sites within the cell which are distant from the site of RNA synthesis, translation of protein from the RNA, splicing of the RNA to yield one or more mRNA species, and catalytic activity which may be engaged in or facilitated by the RNA. The overall effect of such interference with target nucleic acid function is modulation of the expression of SMRT. In the context of the present invention, “modulation” means either an increase (stimulation) or a decrease (inhibition) in the expression of a gene. In the context of the present invention, inhibition is the preferred form of modulation of gene expression and mRNA is a preferred target.

[0021] It is preferred to target specific nucleic acids for antisense. “Targeting” an antisense compound to a particular nucleic acid, in the context of this invention, is a multistep process. The process usually begins with the identification of a nucleic acid sequence whose function is to be modulated. This may be, for example, a cellular gene (or mRNA transcribed from the gene) whose expression is associated with a particular disorder or disease state, or a nucleic acid molecule from an infectious agent. In the present invention, the target is a nucleic acid molecule encoding SMRT. The targeting process also includes determination of a site or sites within this gene for the antisense interaction to occur such that the desired effect, e.g., detection or modulation of expression of the protein, will result. Within the context of the present invention, a preferred intragenic site is the region encompassing the translation initiation or termination codon of the open reading frame (ORF) of the gene. Since, as is known in the art, the translation initiation codon is typically 5′-AUG (in transcribed mRNA molecules; 5′-ATG in the corresponding DNA molecule), the translation initiation codon is also referred to as the “AUG codon,” the “start codon” or the “AUG start codon”. A minority of genes have a translation initiation codon having the RNA sequence 5′-GUG, 5′-UUG or 5′-CUG, and 5′-AUA, 5′-ACG and 5′-CUG have been shown to function in vivo. Thus, the terms “translation initiation codon” and “start codon” can encompass many codon sequences, even though the initiator amino acid in each instance is typically methionine (in eukaryotes) or formylmethionine (in prokaryotes). It is also known in the art that eukaryotic and prokaryotic genes may have two or more alternative start codons, any one of which may be preferentially utilized for translation initiation in a particular cell type or tissue, or under a particular set of conditions. In the context of the invention, “start codon” and “translation initiation codon” refer to the codon or codons that are used in vivo to initiate translation of an mRNA molecule transcribed from a gene encoding SMRT, regardless of the sequence(s) of such codons.

[0022] It is also known in the art that a translation termination codon (or “stop codon”) of a gene may have one of three sequences, i.e., 5′-UAA, 5′-UAG and 5′-UGA (the corresponding DNA sequences are 5′-TAA, 5′-TAG and 5′-TGA, respectively). The terms “start codon region” and “translation initiation codon region“refer to a portion of such an mRNA or gene that encompasses from about 25 to about 50 contiguous nucleotides in either direction (i.e., 5′ or 3′) from a translation initiation codon. Similarly, the terms “stop codon region” and “translation termination codon region” refer to a portion of such an mRNA or gene that encompasses from about 25 to about 50 contiguous nucleotides in either direction (i.e., 5′ or 3′) from a translation termination codon.

[0023] The open reading frame (ORF) or “coding region,” which is known in the art to refer to the region between the translation initiation codon and the translation termination codon, is also a region which may be targeted effectively. Other target regions include the 5′ untranslated region (5′UTR), known in the art to refer to the portion of an mRNA in the 5′ direction from the translation initiation codon, and thus including nucleotides between the 5′ cap site and the translation initiation codon of an mRNA or corresponding nucleotides on the gene, and the 3′ untranslated region (3′UTR), known in the art to refer to the portion of an mRNA in the 3′ direction from the translation termination codon, and thus including nucleotides between the translation termination codon and 3′ end of an mRNA or corresponding nucleotides on the gene. The 5′ cap of an mRNA comprises an N7-methylated guanosine residue joined to the 5′-most residue of the mRNA via a 5′-5′ triphosphate linkage. The 5′ cap region of an mRNA is considered to include the 5′ cap structure itself as well as the first 50 nucleotides adjacent to the cap. The 5′ cap region may also be a preferred target region.

[0024] Although some eukaryotic mRNA transcripts are directly translated, many contain one or more regions, known as “introns,” which are excised from a transcript before it is translated. The remaining (and therefore translated) regions are known as “exons” and are spliced together to form a continuous mRNA sequence. mRNA splice sites, i.e., intron-exon junctions, may also be preferred target regions, and are particularly useful in situations where aberrant splicing is implicated in disease, or where an overproduction of a particular mRNA splice product is implicated in disease. Aberrant fusion junctions due to rearrangements or deletions are also preferred targets. mRNA transcripts produced via the process of splicing of two (or more) mRNAs from different gene sources are known as “fusion transcripts”. It has also been found that introns can be effective, and therefore preferred, target regions for antisense compounds targeted, for example, to DNA or pre-mRNA.

[0025] It is also known in the art that alternative RNA transcripts can be produced from the same genomic region of DNA. These alternative transcripts are generally known as “variants”. More specifically, “pre-mRNA variants” are transcripts produced from the same genomic DNA that differ from other transcripts produced from the same genomic DNA in either their start or stop position and contain both intronic and extronic regions.

[0026] Upon excision of one or more exon or intron regions or portions thereof during splicing, pre-mRNA variants produce smaller “mRNA variants”. Consequently, mRNA variants are processed pre-mRNA variants and each unique pre-mRNA variant must always produce a unique mRNA variant as a result of splicing. These mRNA variants are also known as “alternative splice variants”. If no splicing of the pre-mRNA variant occurs then the pre-mRNA variant is identical to the mRNA variant.

[0027] It is also known in the art that variants can be produced through the use of alternative signals to start or stop transcription and that pre-mRNAs and mRNAs can possess more that one start codon or stop codon. Variants that originate from a pre-mRNA or mRNA that use alternative start codons are known as “alternative start variants” of that pre-mRNA or mRNA. Those transcripts that use an alternative stop codon are known as “alternative stop variants” of that pre-mRNA or mRNA. One specific type of alternative stop variant is the “polyA variant” in which the multiple transcripts produced result from the alternative selection of one of the “polyA stop signals” by the transcription machinery, thereby producing transcripts that terminate at unique polyA sites.

[0028] Once one or more target sites have been identified, oligonucleotides are chosen which are sufficiently complementary to the target, i.e., hybridize sufficiently well and with sufficient specificity, to give the desired effect.

[0029] In the context of this invention, “hybridization” means hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleoside or nucleotide bases. For example, adenine and thymine are complementary nucleobases which pair through the formation of hydrogen bonds. “Complementary,” as used herein, refers to the capacity for precise pairing between two nucleotides. For example, if a nucleotide at a certain position of an oligonucleotide is capable of hydrogen bonding with a nucleotide at the same position of a DNA or RNA molecule, then the oligonucleotide and the DNA or RNA are considered to be complementary to each other at that position. The oligonucleotide and the DNA or RNA are complementary to each other when a sufficient number of corresponding positions in each molecule are occupied by nucleotides which can hydrogen bond with each other Thus, “specifically hybridizable” and “complementary” are terms which are used to indicate a sufficient degree of complementarity or precise pairing such that stable and specific binding occurs between the oligonucleotide and the DNA or RNA target. It is understood in the art that the sequence of an antisense compound need not be 100% complementary to that of its target nucleic acid to be specifically hybridizable.

[0030] An antisense compound is specifically hybridizable when binding of the compound to the target DNA or RNA molecule interferes with the normal function of the target DNA or RNA to cause a loss of activity, and there is a sufficient degree of complementarity to avoid non-specific binding of the antisense compound to non-target sequences under conditions in which specific binding is desired, i.e., under physiological conditions in the case of in vivo assays or therapeutic treatment, and in the case of in vitro assays, under conditions in which the assays are performed. It is preferred that the antisense compounds of the present invention comprise at least 80% sequence complementarity to a target region within the target nucleic acid, moreover that they comprise 90% sequence complementarity and even more comprise 95% sequence complementarity to the target region within the target nucleic acid sequence to which they are targeted. For example, an antisense compound in which 18 of 20 nucleobases of the antisense compound are complementary, and would therefore specifically hybridize, to a target region would represent 90 percent complementarity. Percent complementarity of an antisense compound with a region of a target nucleic acid can be determined routinely using basic local alignment search tools (BLAST programs) (Altschul et al., J. Mol. Biol., 1990, 215, 403-410; Zhang and Madden, Genome Res., 1997, 7, 649-656).

[0031] Antisense and other compounds of the invention, which hybridize to the target and inhibit expression of the target, are identified through experimentation, and representative sequences of these compounds are hereinbelow identified as preferred embodiments of the invention. The sites to which these preferred antisense compounds are specifically hybridizable are hereinbelow referred to as “preferred target regions” and are therefore preferred sites for targeting. As used herein the term “preferred target region” is defined as at least an 8-nucleobase portion of a target region to which an active antisense compound is targeted. While not wishing to be bound by theory, it is presently believed that these target regions represent regions of the target nucleic acid which are accessible for hybridization.

[0032] While the specific sequences of particular preferred target regions are set forth below, one of skill in the art will recognize that these serve to illustrate and describe particular embodiments within the scope of the present invention. Additional preferred target regions may be identified by one having ordinary skill.

[0033] Target regions 8-80 nucleobases in length comprising a stretch of at least eight (8) consecutive nucleobases selected from within the illustrative preferred target regions are considered to be suitable preferred target regions as well.

[0034] Exemplary good preferred target regions include DNA or RNA sequences that comprise at least the 8 consecutive nucleobases from the 5′-terminus of one of the illustrative preferred target regions (the remaining nucleobases being a consecutive stretch of the same DNA or RNA beginning immediately upstream of the 5′-terminus of the target region and continuing until the DNA or RNA contains about 8 to about 80 nucleobases). Similarly good preferred target regions are represented by DNA or RNA sequences that comprise at least the 8 consecutive nucleobases from the 3′-terminus of one of the illustrative preferred target regions (the remaining nucleobases being a consecutive stretch of the same DNA or RNA beginning immediately downstream of the 3′-terminus of the target region and continuing until the DNA or RNA contains about 8 to about 80 nucleobases). One having skill in the art, once armed with the empirically-derived preferred target regions illustrated herein will be able, without undue experimentation, to identify further preferred target regions. In addition, one having ordinary skill in the art will also be able to identify additional compounds, including oligonucleotide probes and primers, that specifically hybridize to these preferred target regions using techniques available to the ordinary practitioner in the art.

[0035] Antisense compounds are commonly used as research reagents and diagnostics. For example, antisense oligonucleotides, which are able to inhibit gene expression with exquisite specificity, are often used by those of ordinary skill to elucidate the function of particular genes. Antisense compounds are also used, for example, to distinguish between functions of various members of a biological pathway. Antisense modulation has, therefore, been harnessed for research use.

[0036] For use in kits and diagnostics, the antisense compounds of the present invention, either alone or in combination with other antisense compounds or therapeutics, can be used as tools in differential and/or combinatorial analyses to elucidate expression patterns of a portion or the entire complement of genes expressed within cells and tissues. Expression patterns within cells or tissues treated with one or more antisense compounds are compared to control cells or tissues not treated with antisense compounds and the patterns produced are analyzed for differential levels of gene expression as they pertain, for example, to disease association, signaling pathway, cellular localization, expression level, size, structure or function of the genes examined. These analyses can be performed on stimulated or unstimulated cells and in the presence or absence of other compounds which affect expression patterns.

[0037] Examples of methods of gene expression analysis known in the art include DNA arrays or microarrays (Brazma and Vilo, FEBS Lett., 2000, 480, 17-24; Celis, et al., FEBS Lett., 2000, 480, 2-16), SAGE (serial analysis of gene expression)(Madden, et al., Drug Discov. Today, 2000, 5, 415-425), READS (restriction enzyme amplification of digested cDNAs) (Prashar and Weissman, Methods Enzymol., 1999, 303, 258-72), TOGA (total gene expression analysis) (Sutcliffe, et al., Proc. Natl. Acad. Sci. U.S.A., 2000, 97, 1976-81), protein arrays and proteomics (Celis, et al., FEBS Lett., 2000, 480, 2-16; Jungblut, et al., Electrophoresis, 1999, 20, 2100-10), expressed sequence tag (EST) sequencing (Celis, et al., FEBS Lett., 2000, 480, 2-16; Larsson, et al., J. Biotechnol., 2000, 80, 143-57), subtractive RNA fingerprinting (SuRF) (Fuchs, et al., Anal. Biochem., 2000, 286, 91-98; Larson, et al., Cytometry, 2000, 41, 203-208), subtractive cloning, differential display (DD) (Jurecic and Belmont, Curr. Opin. Microbiol., 2000, 3, 316-21), comparative genomic hybridization (Carulli, et al., J. Cell Biochem. Suppl., 1998, 31, 286-96), FISH (fluorescent in situ hybridization) techniques (Going and Gusterson, Eur. J. Cancer, 1999, 35, 1895-904) and mass spectrometry methods (reviewed in To, Comb. Chem. High Throughput Screen, 2000, 3, 235-41).

[0038] The specificity and sensitivity of antisense is also harnessed by those of skill in the art for therapeutic uses. Antisense oligonucleotides have been employed as therapeutic moieties in the treatment of disease states in animals and man. Antisense oligonucleotide drugs, including ribozymes, have been safely and effectively administered to humans and numerous clinical trials are presently underway. It is thus established that oligonucleotides can be useful therapeutic modalities that can be configured to be useful in treatment regimes for treatment of cells, tissues and animals, especially humans.

[0039] In the context of this invention, the term “oligonucleotide” refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimetics thereof. This term includes oligonucleotides composed of naturally-occurring nucleobases, sugars and covalent internucleoside (backbone) linkages as well as oligonucleotides having non-naturally-occurring portions which function similarly. Such modified or substituted oligonucleotides are often preferred over native forms because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for nucleic acid target and increased stability in the presence of nucleases.

[0040] While antisense oligonucleotides are a preferred form of antisense compound, the present invention comprehends other oligomeric antisense compounds, including but not limited to oligonucleotide mimetics such as are described below. The antisense compounds in accordance with this invention preferably comprise from about 8 to about 80 nucleobases (i.e. from about 8 to about 80 linked nucleosides). Particularly preferred antisense compounds are antisense oligonucleotides from about 8 to about 50 nucleobases, even more preferably those comprising from about 12 to about 30 nucleobases. Antisense compounds include ribozymes, external guide sequence (EGS) oligonucleotides (oligozymes), and other short catalytic RNAs or catalytic oligonucleotides which hybridize to the target nucleic acid and modulate its expression.

[0041] Antisense compounds 8-80 nucleobases in length comprising a stretch of at least eight (8) consecutive nucleobases selected from within the illustrative antisense compounds are considered to be suitable antisense compounds as well.

[0042] Exemplary preferred antisense compounds include DNA or RNA sequences that comprise at least the 8 consecutive nucleobases from the 5′-terminus of one of the illustrative preferred antisense compounds (the remaining nucleobases being a consecutive stretch of the same DNA or RNA beginning immediately upstream of the 5′-terminus of the antisense compound which is specifically hybridizable to the target nucleic acid and continuing until the DNA or RNA contains about 8 to about 80 nucleobases). Similarly preferred antisense compounds are represented by DNA or RNA sequences that comprise at least the 8 consecutive nucleobases from the 3′-terminus of one of the illustrative preferred antisense compounds (the remaining nucleobases being a consecutive stretch of the same DNA or RNA beginning immediately downstream of the 3′-terminus of the antisense compound which is specifically hybridizable to the target nucleic acid and continuing until the DNA or RNA contains about 8 to about 80 nucleobases). One having skill in the art, once armed with the empirically-derived preferred antisense compounds illustrated herein will be able, without undue experimentation, to identify further preferred antisense compounds.

[0043] Antisense and other compounds of the invention, which hybridize to the target and inhibit expression of the target, are identified through experimentation, and representative sequences of these compounds are herein identified as preferred embodiments of the invention. While specific sequences of the antisense compounds are set forth herein, one of skill in the art will recognize that these serve to illustrate and describe particular embodiments within the scope of the present invention. Additional preferred antisense compounds may be identified by one having ordinary skill.

[0044] As is known in the art, a nucleoside is a base-sugar combination. The base portion of the nucleoside is normally a heterocyclic base. The two most common classes of such heterocyclic bases are the purines and the pyrimidines. Nucleotides are nucleosides that further include a phosphate group covalently linked to the sugar portion of the nucleoside. For those nucleosides that include a pentofuranosyl sugar, the phosphate group can be linked to either the 2′, 3′ or 5′ hydroxyl moiety of the sugar. In forming oligonucleotides, the phosphate groups covalently link adjacent nucleosides to one another to form a linear polymeric compound. In turn, the respective ends of this linear polymeric structure can be further joined to form a circular structure, however, open linear structures are generally preferred. In addition, linear structures may also have internal nucleobase complementarity and may therefore fold in a manner as to produce a double stranded structure. Within the oligonucleotide structure, the phosphate groups are commonly referred to as forming the internucleoside backbone of the oligonucleotide. The normal linkage or backbone of RNA and DNA is a 3′ to 5′ phosphodiester linkage.

[0045] Specific examples of preferred antisense compounds useful in this invention include oligonucleotides containing modified backbones or non-natural internucleoside linkages. As defined in this specification, oligonucleotides having modified backbones include those that retain a phosphorus atom in the backbone and those that do not have a phosphorus atom in the backbone. For the purposes of this specification, and as sometimes referenced in the art, modified oligonucleotides that do not have a phosphorus atom in their internucleoside backbone can also be considered to be oligonucleosides.

[0046] Preferred modified oligonucleotide backbones include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotri-esters, methyl and other alkyl phosphonates including 3′-alkylene phosphonates, 5′-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3′-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, selenophosphates and borano-phosphates having normal 3′-5′ linkages, 2′-5′ linked analogs of these, and those having inverted polarity wherein one or more internucleotide linkages is a 3′ to 3′, 5′ to 5′ or 2′ to 2′ linkage. Preferred oligonucleotides having inverted polarity comprise a single 3′ to 3′ linkage at the 3′-most internucleotide linkage i.e. a single inverted nucleoside residue which may be abasic (the nucleobase is missing or has a hydroxyl group in place thereof). Various salts, mixed salts and free acid forms are also included.

[0047] Representative United States patents that teach the preparation of the above phosphorus-containing linkages include, but are not limited to, U.S. Pat. Nos. : 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5,177,196; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,306; 5,550,111; 5,563,253; 5,571,799; 5,587,361; 5,194,599; 5,565,555; 5,527,899; 5,721,218; 5,672,697 and 5,625,050, certain of which are commonly owned with this application, and each of which is herein incorporated by reference.

[0048] Preferred modified oligonucleotide backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; riboacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and CH₂ component parts.

[0049] Representative United States patents that teach the preparation of the above oligonucleosides include, but are not limited to, U.S. Pat. Nos.: 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,264,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,610,289; 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360; 5,677,437; 5,792,608; 5,646,269 and 5,677,439, certain of which are commonly owned with this application, and each of which is herein incorporated by reference.

[0050] In other preferred oligonucleotide mimetics, both the sugar and the internucleoside linkage, i.e., the backbone, of the nucleotide units are replaced with novel groups. The base units are maintained for hybridization with an appropriate nucleic acid target compound. One such oligomeric compound, an oligonucleotide mimetic that has been shown to have excellent hybridization properties, is referred to as a peptide nucleic acid (PNA). In PNA compounds, the sugar-backbone of an oligonucleotide is replaced with an amide containing backbone, in particular an aminoethylglycine backbone. The nucleobases are retained and are bound directly or indirectly to aza nitrogen atoms of the amide portion of the backbone. Representative United States patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Pat. Nos.: 5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference. Further teaching of PNA compounds can be found in Nielsen et al., Science, 1991, 254, 1497-1500.

[0051] Most preferred embodiments of the invention are oligonucleotides with phosphorothioate backbones and oligonucleosides with heteroatom backbones, and in particular —CH₂—NH—O—CH₂—, —CH₂—N(CH₃)—O—CH₂— [known as a methylene (methylimino) or MMI backbone], —CH₂—O—N(CH₃)—CH₂—, —CH₂—N(CH₃)—N(CH₃)—CH₂— and —O—N(CH₃)—CH₂—CH₂— [wherein the native phosphodiester backbone is represented as —O—P—O—CH₂—] of the above referenced U.S. Pat. No. 5,489,677, and the amide backbones of the above referenced U.S. Pat. No. 5,602,240. Also preferred are oligonucleotides having morpholino backbone structures of the above-referenced U.S. Pat. No. 5,034,506.

[0052] Modified oligonucleotides may also contain one or more substituted sugar moieties. Preferred oligonucleotides comprise one of the following at the 2′ position: OH; F; O—, S—, or N-alkyl; O—, S—, or N-alkenyl; O—, S— or N-alkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl may be substituted or unsubstituted C₁ to C₁₀ alkyl or C₂ to C₁₀ alkenyl and alkynyl. Particularly preferred are O[(CH₂)_(n)O]_(m)CH₃, O(CH₂)_(n)OCH₃, O(CH₂)_(n)NH₂, O(CH₂)_(n)CH₃, O(CH₂)_(n)ONH₂, and O(CH₂)_(n)ON[(CH₂)_(n)CH₃]₂, where n and m are from 1 to about 10. Other preferred oligonucleotides comprise one of the following at the 2′ position: C₁ to C₁₀ lower alkyl, substituted lower alkyl, alkenyl, alkynyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH₃, OCN, Cl, Br, CN, CF₃, OCF₃, SOCH₃, SO₂CH₃, ONO₂, NO₂, N₃, NH₂, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties of an oligonucleotide, or a group for improving the pharmacodynamic properties of an oligonucleotide, and other substituents having similar properties. A preferred modification includes 2′-methoxyethoxy (2′-O—CH₂CH₂OCH₃, also known as 2′-O-(2-methoxyethyl) or 2′-MOE) (Martin et al., Helv. Chim. Acta, 1995, 78, 486-504) i.e., an alkoxyalkoxy group. A further preferred modification includes 2′-dimethylaminooxyethoxy, i.e., a O(CH₂)₂ON(CH₃)₂ group, also known as 2′-DMAOE, as described in examples hereinbelow, and 2′-dimethylaminoethoxyethoxy (also known in the art as 2′-O-dimethyl-amino-ethoxy-ethyl or 2′-DMAEOE), i.e., 2′-O—CH₂—O—CH₂—N(CH₃)₂, also described in examples hereinbelow.

[0053] Other preferred modifications include 2′-methoxy (2′-O—CH₃), 2′-aminopropoxy (2′-OCH₂CH₂CH₂NH₂), 2′-allyl (2′—CH₂—CH═CH₂), 2′-O-allyl (2′-O—CH₂—CH═CH₂) and 2′-fluoro (2′-F). The 2′-modification may be in the arabino (up) position or ribo (down) position. A preferred 2′-arabino modification is 2′-F. Similar modifications may also be made at other positions on the oligonucleotide, particularly the 3′ position of the sugar on the 3′ terminal nucleotide or in 2′-5′ linked oligonucleotides and the 5′ position of 5′ terminal nucleotide. Oligonucleotides may also have sugar mimetics such as cyclobutyl moieties in place of the pentofuranosyl sugar. Representative United States patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Pat. Nos.: 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; 5,792,747; and 5,700,920, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference in its entirety.

[0054] A further preferred modification includes Locked Nucleic Acids (LNAs) in which the 2′-hydroxyl group is linked to the 3′ or 4′ carbon atom of the sugar ring thereby forming a bicyclic sugar moiety. The linkage is preferably a methelyne (—CH₂—)_(n) group bridging the 2′ oxygen atom and the 4′ carbon atom wherein n is 1 or 2. LNAs and preparation thereof are described in WO 98/39352 and WO 99/14226.

[0055] Oligonucleotides may also include nucleobase (often referred to in the art simply as “base”) modifications or substitutions. As used herein, “unmodified” or “natural” nucleobases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). Modified nucleobases include other synthetic and natural nucleobases such as 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl (—C≡C—CH₃)uracil and cytosine and other alkynyl derivatives of pyrimidine bases, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 2-F-adenine, 2-amino-adenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine. Further modified nucleobases include tricyclic pyrimidines such as phenoxazine cytidine(1H-pyrimido[5,4-b][1,4]benzoxazin-2(3H)-one), phenothiazine cytidine(1H-pyrimido[5,4-b][1,4]benzothiazin-2(3H)-one), G-clamps such as a substituted phenoxazine cytidine (e.g. 9-(2-aminoethoxy)-H-pyrimido[5,4-b][1,4]benzoxazin-2(3H)-one), carbazole cytidine (2H-pyrimido[4,5-b]indol-2-one), pyridoindole cytidine (H-pyrido[3′,2′:4,5]pyrrolo[2,3-d]pyrimidin-2-one). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucleobases include those disclosed in U.S. Pat. No. 3,687,808, those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859, Kroschwitz, J. I., ed. John Wiley & Sons, 1990, those disclosed by Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613, and those disclosed by Sanghvi, Y. S., Chapter 15, Antisense Research and Applications, pages 289-302, Crooke, S. T. and Lebleu, B., ed., CRC Press, 1993. Certain of these nucleobases are particularly useful for increasing the binding affinity of the oligomeric compounds of the invention. These include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and O-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine. 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2° C. (Sanghvi, Y. S., Crooke, S. T. and Lebleu, B., eds., Antisense Research and Applications, CRC Press, Boca Raton, 1993, pp. 276-278) and are presently preferred base substitutions, even more particularly when combined with 2′-O-methoxyethyl sugar modifications.

[0056] Representative United States patents that teach the preparation of certain of the above noted modified nucleobases as well as other modified nucleobases include, but are not limited to, the above noted U.S. Pat. No. 3,687,808, as well as U.S. Pat. Nos.: 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121, 5,596,091; 5,614,617; 5,645,985; 5,830,653; 5,763,588; 6,005,096; and 5,681,941, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference, and U.S. Pat. No. 5,750,692, which is commonly owned with the instant application and also herein incorporated by reference.

[0057] Another modification of the oligonucleotides of the invention involves chemically linking to the oligonucleotide one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. The compounds of the invention can include conjugate groups covalently bound to functional groups such as primary or secondary hydroxyl groups. Conjugate groups of the invention include intercalators, reporter molecules, polyamines, polyamides, polyethylene glycols, polyethers, groups that enhance the pharmacodynamic properties of oligomers, and groups that enhance the pharmacokinetic properties of oligomers. Typical conjugate groups include cholesterols, lipids, phospholipids, biotin, phenazine, folate, phenanthridine, anthraquinone, acridine, fluores-ceins, rhodamines, coumarins, and dyes. Groups that enhance the pharmacodynamic properties, in the context of this invention, include groups that improve oligomer uptake, enhance oligomer resistance to degradation, and/or strengthen sequence-specific hybridization with RNA. Groups that enhance the pharmacokinetic properties, in the context of this invention, include groups that improve oligomer uptake, distribution, metabolism or excretion Representative conjugate groups are disclosed in International Patent Application PCT/US92/09196, filed Oct. 23, 1992 the entire disclosure of which is incorporated herein by reference. Conjugate moieties include but are not limited to lipid moieties such as a cholesterol moiety (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan et al., Bioorg. Med. Chem. Let., 1994, 4, 1053-1060), a thioether, e.g., hexyl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660, 306-309; Manoharan et al., Bioorg. Med. Chem. Let., 1993, 3, 2765-2770), a thiocholesterol, (Oberhauser et al., Nucl. Acids Res., 1992, 20, 533-538), an aliphatic chain, e.g., dodecandiol or undecyl residues (Saison-Behmoaras et al., EMBO J., 1991, 10, 1111-1118; Kabanov et al., FEBS Lett., 1990, 259, 327-330; Svinarchuk et al., Biochimie, 1993, 75, 49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654; Shea et al., Nucl. Acids Res., 1990, 18, 3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14, 969-973), or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654), a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264, 229-237), or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277, 923-937). Oligonucleotides of the invention may also be conjugated to active drug substances, for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fenbufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, flufenamic acid, folinic acid, a benzothiadiazide, chlorothiazide, a diazepine, indomethicin, a barbiturate, a cephalosporin, a sulfa drug, an antidiabetic, an antibacterial or an antibiotic. Oligonucleotide-drug conjugates and their preparation are described in U.S. patent application Ser. No. 09/334,130 (filed Jun. 15, 1999) which is incorporated herein by reference in its entirety.

[0058] Representative United States patents that teach the preparation of such oligonucleotide conjugates include, but are not limited to, U.S. Pat. Nos.: 4,828,979; 4,948,882; 5,218,105; 5,525,465; 5,541,313; 5,545,730; 5,552,538; 5,578,717, 5,580,731; 5,580,731; 5,591,584; 5,109,124; 5,118,802; 5,138,045; 5,414,077; 5,486,603; 5,512,439; 5,578,718; 5,608,046; 4,587,044; 4,605,735; 4,667,025; 4,762,779; 4,789,737; 4,824,941; 4,835,263; 4,876,335; 4,904,582; 4,958,013; 5,082,830; 5,112,963; 5,214,136; 5,082,830; 5,112,963; 5,214,136; 5,245,022; 5,254,469; 5,258,506; 5,262,536; 5,272,250; 5,292,873; 5,317,098; 5,371,241, 5,391,723; 5,416,203, 5,451,463; 5,510,475; 5,512,667; 5,514,785; 5,565,552; 5,567,810; 5,574,142; 5,585,481; 5,587,371; 5,595,726; 5,597,696; 5,599,923; 5,599,928 and 5,688,941, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference.

[0059] It is not necessary for all positions in a given compound to be uniformly modified, and in fact more than one of the aforementioned modifications may be incorporated in a single compound or even at a single nucleoside within an oligonucleotide. The present invention also includes antisense compounds which are chimeric compounds. “Chimeric” antisense compounds or “chimeras,” in the context of this invention, are antisense compounds, particularly oligonucleotides, which contain two or more chemically distinct regions, each made up of at least one monomer unit, i.e., a nucleotide in the case of an oligonucleotide compound. These oligonucleotides typically contain at least one region wherein the oligonucleotide is modified so as to confer upon the oligonucleotide increased resistance to nuclease degradation, increased cellular uptake, increased stability and/or increased binding affinity for the target nucleic acid. An additional region of the oligonucleotide may serve as a substrate for enzymes capable of cleaving RNA:DNA or RNA:RNA hybrids. By way of example, RNAse H is a cellular endonuclease which cleaves the RNA strand of an RNA:DNA duplex. Activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of oligonucleotide inhibition of gene expression. The cleavage of RNA:RNA hybrids can, in like fashion, be accomplished through the actions of endoribonucleases, such as interferon-induced RNAseL which cleaves both cellular and viral RNA. Consequently, comparable results can often be obtained with shorter oligonucleotides when chimeric oligonucleotides are used, compared to phosphorothioate deoxyoligonucleotides hybridizing to the same target region. Cleavage of the RNA target can be routinely detected by gel electrophoresis and, if necessary, associated nucleic acid hybridization techniques known in the art.

[0060] Chimeric antisense compounds of the invention may be formed as composite structures of two or more oligonucleotides, modified oligonucleotides, oligonucleosides and/or oligonucleotide mimetics as described above. Such compounds have also been referred to in the art as hybrids or gapmers. Representative United States patents that teach the preparation of such hybrid structures include, but are not limited to, U.S. Pat. Nos.: 5,013,830; 5,149,797; 5,220,007; 5,256,775; 5,366,878; 5,403,711; 5,491,133; 5,565,350; 5,623,065; 5,652,355; 5,652,356; and 5,700,922, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference in its entirety.

[0061] The antisense compounds used in accordance with this invention may be conveniently and routinely made through the well-known technique of solid phase synthesis. Equipment for such synthesis is sold by several vendors including, for example, Applied Biosystems (Foster City, Calif.). Any other means for such synthesis known in the art may additionally or alternatively be employed. It is well known to use similar techniques to prepare oligonucleotides such as the phosphorothioates and alkylated derivatives.

[0062] The compounds of the invention may also be admixed, encapsulated, conjugated or otherwise associated with other molecules, molecule structures or mixtures of compounds, as for example, liposomes, receptor-targeted molecules, oral, rectal, topical or other formulations, for assisting in uptake, distribution and/or absorption. Representative United States patents that teach the preparation of such uptake, distribution and/or absorption-assisting formulations include, but are not limited to, U.S. Pat. Nos.: 5,108,921; 5,354,844; 5,416,016; 5,459,127; 5,521,291; 5,543,158; 5,547,932; 5,583,020; 5,591,721; 4,426,330; 4,534,899; 5,013,556; 5,108,921; 5,213,804; 5,227,170; 5,264,221; 5,356,633; 5,395,619; 5,416,016; 5,417,978; 5,462,854; 5,469,854; 5,512,295; 5,527,528; 5,534,259; 5,543,152; 5,556,948; 5,580,575; and 5,595,756, each of which is herein incorporated by reference.

[0063] The antisense compounds of the invention encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other compound which, upon administration to an animal, including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to prodrugs and pharmaceutically acceptable salts of the compounds of the invention, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents.

[0064] The term “prodrug” indicates a therapeutic agent that is prepared in an inactive form that is converted to an active form (i.e., drug) within the body or cells thereof by the action of endogenous enzymes or other chemicals and/or conditions. In particular, prodrug versions of the oligonucleotides of the invention are prepared as SATE [(S-acetyl-2-thioethyl)phosphate] derivatives according to the methods disclosed in WO 93/24510 to Gosselin et al., published Dec. 9, 1993 or in WO 94/26764 and U.S. Pat. No. 5,770,713 to Imbach et al.

[0065] The term “pharmaceutically acceptable salts” refers to physiologically and pharmaceutically acceptable salts of the compounds of the invention: i.e., salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto.

[0066] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge et al., “Pharmaceutical Salts,” J. of Pharma Sci., 1977, 66, 1-19). The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention. As used herein, a “pharmaceutical addition salt” includes a pharmaceutically acceptable salt of an acid form of one of the components of the compositions of the invention. These include organic or inorganic acid salts of the amines. Preferred acid salts are the hydrochlorides, acetates, salicylates, nitrates and phosphates. Other suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of a variety of inorganic and organic acids, such as, for example, with inorganic acids, such as for example hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; with organic carboxylic, sulfonic, sulfo or phospho acids or N-substituted sulfamic acids, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, lactic acid, oxalic acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid; and with amino acids, such as the 20 alpha-amino acids involved in the synthesis of proteins in nature, for example glutamic acid or aspartic acid, and also with phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 2- or 3-phosphoglycerate, glucose-6-phosphate, N-cyclohexylsulfamic acid (with the formation of cyclamates), or with other acid organic compounds, such as ascorbic acid. Pharmaceutically acceptable salts of compounds may also be prepared with a pharmaceutically acceptable cation. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations. Carbonates or hydrogen carbonates are also possible.

[0067] For oligonucleotides, preferred examples of pharmaceutically acceptable salts include but are not limited to (a) salts formed with cations such as sodium, potassium, ammonium, magnesium, calcium, polyamines such as spermine and spermidine, etc.; (b) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; (c) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; and (d) salts formed from elemental anions such as chlorine, bromine, and iodine.

[0068] The antisense compounds of the present invention can be utilized for diagnostics, therapeutics, prophylaxis and as research reagents and kits. For therapeutics, an animal, preferably a human, suspected of having a disease or disorder which can be treated by modulating the expression of SMRT is treated by administering antisense compounds in accordance with this invention. The compounds of the invention can be utilized in pharmaceutical compositions by adding an effective amount of an antisense compound to a suitable pharmaceutically acceptable diluent or carrier. Use of the antisense compounds and methods of the invention may also be useful prophylactically, e.g., to prevent or delay infection, inflammation or tumor formation, for example.

[0069] The antisense compounds of the invention are useful for research and diagnostics, because these compounds hybridize to nucleic acids encoding SMRT, enabling sandwich and other assays to easily be constructed to exploit this fact. Hybridization of the antisense oligonucleotides of the invention with a nucleic acid encoding SMRT can be detected by means known in the art. Such means may include conjugation of an enzyme to the oligonucleotide, radiolabelling of the oligonucleotide or any other suitable detection means. Kits using such detection means for detecting the level of SMRT in a sample may also be prepared.

[0070] The present invention also includes pharmaceutical compositions and formulations which include the antisense compounds of the invention. The pharmaceutical compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary, e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Oligonucleotides with at least one 2′-O-methoxyethyl modification are believed to be particularly useful for oral administration.

[0071] Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Coated condoms, gloves and the like may also be useful. Preferred topical formulations include those in which the oligonucleotides of the invention are in admixture with a topical delivery agent such as lipids, liposomes, fatty acids, fatty acid esters, steroids, chelating agents and surfactants. Preferred lipids and liposomes include neutral (e.g. dioleoylphosphatidyl DOPE ethanolamine, dimyristoylphosphatidyl choline DMPC, distearolyphosphatidyl choline) negative (e.g. dimyristoylphosphatidyl glycerol DMPG) and cationic (e.g. dioleoyltetramethylaminopropyl DOTAP and dioleoylphosphatidyl ethanolamine DOTMA). Oligonucleotides of the invention may be encapsulated within liposomes or may form complexes thereto, in particular to cationic liposomes. Alternatively, oligonucleotides may be complexed to lipids, in particular to cationic lipids. Preferred fatty acids and esters include but are not limited arachidonic acid, oleic acid, eicosanoic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein, dilaurin, glyceryl 1-monocaprate, 1-dodecylazacycloheptan-2-one, an acylcarnitine, an acylcholine, or a C₁₋₁₀ alkyl ester (e.g. isopropylmyristate IPM), monoglyceride, diglyceride or pharmaceutically acceptable salt thereof. Topical formulations are described in detail in U.S. patent application Ser. No. 09/315,298 filed on May 20, 1999 which is incorporated herein by reference in its entirety.

[0072] Compositions and formulations for oral administration include powders or granules, microparticulates, nanoparticulates, suspensions or solutions in water or non-aqueous media, capsules, gel capsules, sachets, tablets or minitablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders may be desirable. Preferred oral formulations are those in which oligonucleotides of the invention are administered in conjunction with one or more penetration enhancers surfactants and chelators. Preferred surfactants include fatty acids and/or esters or salts thereof, bile acids and/or salts thereof. Preferred bile acids/salts include chenodeoxycholic acid (CDCA) and ursodeoxychenodeoxycholic acid (UDCA), cholic acid, dehydrocholic acid, deoxycholic acid, glucholic acid, glycholic acid, glycodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, sodium tauro-24,25-dihydro-fusidate and sodium glycodihydrofusidate. Preferred fatty acids include arachidonic acid, undecanoic acid, oleic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein, dilaurin, glyceryl 1-monocaprate, 1-dodecylazacycloheptan-2-one, an acylcarnitine, an acylcholine, or a monoglyceride, a diglyceride or a pharmaceutically acceptable salt thereof (e.g. sodium). Also preferred are combinations of penetration enhancers, for example, fatty acids/salts in combination with bile acids/salts. A particularly preferred combination is the sodium salt of lauric acid, capric acid and UDCA. Further penetration enhancers include polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether. Oligonucleotides of the invention may be delivered orally, in granular form including sprayed dried particles, or complexed to form micro or nanoparticles. Oligonucleotide complexing agents include poly-amino acids; polyimines; polyacrylates; polyalkylacrylates, polyoxethanes, polyalkylcyanoacrylates; cationized gelatins, albumins, starches, acrylates, polyethyleneglycols (PEG) and starches; polyalkylcyanoacrylates; DEAE-derivatized polyimines, pollulans, celluloses and starches. Particularly preferred complexing agents include chitosan, N-trimethylchitosan, poly-L-lysine, polyhistidine, polyornithine, polyspermines, protamine, polyvinylpyridine, polythiodiethylamino-methylethylene P(TDAE), polyaminostyrene (e.g. p-amino), poly(methylcyanoacrylate), poly(ethylcyanoacrylate), poly(butylcyanoacrylate), poly(isobutylcyanoacrylate), poly(isohexylcynaoacrylate), DEAE-methacrylate, DEAE-hexylacrylate, DEAE-acrylamide, DEAE-albumin and DEAE-dextran, polymethylacrylate, polyhexylacrylate, poly(D,L-lactic acid), poly(DL-lactic-co-glycolic acid (PLGA), alginate, and polyethyleneglycol (PEG). Oral formulations for oligonucleotides and their preparation are described in detail in U.S. application Ser. Nos. 08/886,829 (filed Jul. 1, 1997), 09/108,673 (filed Jul. 1, 1998), 09/256,515 (filed Feb. 23, 1999), 09/082,624 (filed May 21, 1998) and 09/315,298 (filed May 20, 1999), each of which is incorporated herein by reference in their entirety.

[0073] Compositions and formulations for parenteral, intrathecal or intraventricular administration may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients.

[0074] Pharmaceutical compositions of the present invention include, but are not limited to, solutions, emulsions, and liposome-containing formulations. These compositions may be generated from a variety of components that include, but are not limited to, preformed liquids, self-emulsifying solids and self-emulsifying semisolids.

[0075] The pharmaceutical formulations of the present invention, which may conveniently be presented in unit dosage form, may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0076] The compositions of the present invention may be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, gel capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present invention may also be formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions may further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension may also contain stabilizers.

[0077] In one embodiment of the present invention the pharmaceutical compositions may be formulated and used as foams. Pharmaceutical foams include formulations such as, but not limited to, emulsions, microemulsions, creams, jellies and liposomes. While basically similar in nature these formulations vary in the components and the consistency of the final product. The preparation of such compositions and formulations is generally known to those skilled in the pharmaceutical and formulation arts and may be applied to the formulation of the compositions of the present invention.

[0078] Emulsions

[0079] The compositions of the present invention may be prepared and formulated as emulsions. Emulsions are typically heterogenous systems of one liquid dispersed in another in the form of droplets usually exceeding 0.1 μm in diameter (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199; Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., Volume 1, p. 245; Block in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 2, p. 335; Higuchi et al., in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1985, p. 301). Emulsions are often biphasic systems comprising two immiscible liquid phases intimately mixed and dispersed with each other. In general, emulsions may be of either the water-in-oil (w/o) or the oil-in-water (o/w) variety. When an aqueous phase is finely divided into and dispersed as minute droplets into a bulk oily phase, the resulting composition is called a water-in-oil (w/o) emulsion. Alternatively, when an oily phase is finely divided into and dispersed as minute droplets into a bulk aqueous phase, the resulting composition is called an oil-in-water (o/w) emulsion. Emulsions may contain additional components in addition to the dispersed phases, and the active drug which may be present as a solution in either the aqueous phase, oily phase or itself as a separate phase. Pharmaceutical excipients such as emulsifiers, stabilizers, dyes, and anti-oxidants may also be present in emulsions as needed. Pharmaceutical emulsions may also be multiple emulsions that are comprised of more than two phases such as, for example, in the case of oil-in-water-in-oil (o/w/o) and water-in-oil-in-water (w/o/w) emulsions. Such complex formulations often provide certain advantages that simple binary emulsions do not. Multiple emulsions in which individual oil droplets of an o/w emulsion enclose small water droplets constitute a w/o/w emulsion. Likewise a system of oil droplets enclosed in globules of water stabilized in an oily continuous phase provides an o/w/o emulsion.

[0080] Emulsions are characterized by little or no thermodynamic stability. Often, the dispersed or discontinuous phase of the emulsion is well dispersed into the external or continuous phase and maintained in this form through the means of emulsifiers or the viscosity of the formulation. Either of the phases of the emulsion may be a semisolid or a solid, as is the case of emulsion-style ointment bases and creams. Other means of stabilizing emulsions entail the use of emulsifiers that may be incorporated into either phase of the emulsion. Emulsifiers may broadly be classified into four categories: synthetic surfactants, naturally occurring emulsifiers, absorption bases, and finely dispersed solids (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199).

[0081] Synthetic surfactants, also known as surface active agents, have found wide applicability in the formulation of emulsions and have been reviewed in the literature (Rieger, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 285; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), Marcel Dekker, Inc., New York, N.Y., 1988, volume 1, p. 199). Surfactants are typically amphiphilic and comprise a hydrophilic and a hydrophobic portion. The ratio of the hydrophilic to the hydrophobic nature of the surfactant has been termed the hydrophile/lipophile balance (HLB) and is a valuable tool in categorizing and selecting surfactants in the preparation of formulations. Surfactants may be classified into different classes based on the nature of the hydrophilic group: nonionic, anionic, cationic and amphoteric (Rieger, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 285).

[0082] Naturally occurring emulsifiers used in emulsion formulations include lanolin, beeswax, phosphatides, lecithin and acacia. Absorption bases possess hydrophilic properties such that they can soak up water to form w/o emulsions yet retain their semisolid consistencies, such as anhydrous lanolin and hydrophilic petrolatum. Finely divided solids have also been used as good emulsifiers especially in combination with surfactants and in viscous preparations. These include polar inorganic solids, such as heavy metal hydroxides, nonswelling clays such as bentonite, attapulgite, hectorite, kaolin, montmorillonite, colloidal aluminum silicate and colloidal magnesium aluminum silicate, pigments and nonpolar solids such as carbon or glyceryl tristearate.

[0083] A large variety of non-emulsifying materials are also included in emulsion formulations and contribute to the properties of emulsions. These include fats, oils, waxes, fatty acids, fatty alcohols, fatty esters, humectants, hydrophilic colloids, preservatives and antioxidants (Block, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 335; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199).

[0084] Hydrophilic colloids or hydrocolloids include naturally occurring gums and synthetic polymers such as polysaccharides (for example, acacia, agar, alginic acid, carrageenan, guar gum, karaya gum, and tragacanth), cellulose derivatives (for example, carboxymethylcellulose and carboxypropylcellulose), and synthetic polymers (for example, carbomers, cellulose ethers, and carboxyvinyl polymers). These disperse or swell in water to form colloidal solutions that stabilize emulsions by forming strong interfacial films around the dispersed-phase droplets and by increasing the viscosity of the external phase.

[0085] Since emulsions often contain a number of ingredients such as carbohydrates, proteins, sterols and phosphatides that may readily support the growth of microbes, these formulations often incorporate preservatives. Commonly used preservatives included in emulsion formulations include methyl paraben, propyl paraben, quaternary ammonium salts, benzalkonium chloride, esters of p-hydroxybenzoic acid, and boric acid. Antioxidants are also commonly added to emulsion formulations to prevent deterioration of the formulation. Antioxidants used may be free radical scavengers such as tocopherols, alkyl gallates, butylated hydroxyanisole, butylated hydroxytoluene, or reducing agents such as ascorbic acid and sodium metabisulfite, and antioxidant synergists such as citric acid, tartaric acid, and lecithin.

[0086] The application of emulsion formulations via dermatological, oral and parenteral routes and methods for their manufacture have been reviewed in the literature (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). Emulsion formulations for oral delivery have been very widely used because of ease of formulation, as well as efficacy from an absorption and bioavailability standpoint (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). Mineral-oil base laxatives, oil-soluble vitamins and high fat nutritive preparations are among the materials that have commonly been administered orally as o/w emulsions.

[0087] In one embodiment of the present invention, the compositions of oligonucleotides and nucleic acids are formulated as microemulsions. A microemulsion may be defined as a system of water, oil and amphiphile which is a single optically isotropic and thermodynamically stable liquid solution (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245). Typically microemulsions are systems that are prepared by first dispersing an oil in an aqueous surfactant solution and then adding a sufficient amount of a fourth component, generally an intermediate chain-length alcohol to form a transparent system. Therefore, microemulsions have also been described as thermodynamically stable, isotropically clear dispersions of two immiscible liquids that are stabilized by interfacial films of surface-active molecules (Leung and Shah, in: Controlled Release of Drugs: Polymers and Aggregate Systems, Rosoff, M., Ed., 1989, VCH Publishers, New York, pages 185-215). Microemulsions commonly are prepared via a combination of three to five components that include oil, water, surfactant, cosurfactant and electrolyte. Whether the microemulsion is of the water-in-oil (w/o) or an oil-in-water (o/w) type is dependent on the properties of the oil and surfactant used and on the structure and geometric packing of the polar heads and hydrocarbon tails of the surfactant molecules (Schott, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1985, p. 271).

[0088] The phenomenological approach utilizing phase diagrams has been extensively studied and has yielded a comprehensive knowledge, to one skilled in the art, of how to formulate microemulsions (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245; Block, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 335). Compared to conventional emulsions, microemulsions offer the advantage of solubilizing water-insoluble drugs in a formulation of thermodynamically stable droplets that are formed spontaneously.

[0089] Surfactants used in the preparation of microemulsions include, but are not limited to, ionic surfactants, non-ionic surfactants, Brij 96, polyoxyethylene oleyl ethers, polyglycerol fatty acid esters, tetraglycerol monolaurate (ML310), tetraglycerol monooleate (MO310), hexaglycerol monooleate (PO310), hexaglycerol pentaoleate (PO500), decaglycerol monocaprate (MCA750), decaglycerol monooleate (MO750), decaglycerol sequioleate (SO750), decaglycerol decaoleate (DAO750), alone or in combination with cosurfactants. The cosurfactant, usually a short-chain alcohol such as ethanol, 1-propanol, and 1-butanol, serves to increase the interfacial fluidity by penetrating into the surfactant film and consequently creating a disordered film because of the void space generated among surfactant molecules. Microemulsions may, however, be prepared without the use of cosurfactants and alcohol-free self-emulsifying microemulsion systems are known in the art. The aqueous phase may typically be, but is not limited to, water, an aqueous solution of the drug, glycerol, PEG300, PEG400, polyglycerols, propylene glycols, and derivatives of ethylene glycol. The oil phase may include, but is not limited to, materials such as Captex 300, Captex 355, Capmul MCM, fatty acid esters, medium chain (C8-C12) mono, di, and tri-glycerides, polyoxyethylated glyceryl fatty acid esters, fatty alcohols, polyglycolized glycerides, saturated polyglycolized C8-C10 glycerides, vegetable oils and silicone oil.

[0090] Microemulsions are particularly of interest from the standpoint of drug solubilization and the enhanced absorption of drugs. Lipid based microemulsions (both o/w and w/o) have been proposed to enhance the oral bioavailability of drugs, including peptides (Constantinides et al., Pharmaceutical Research, 1994, 11, 1385-1390; Ritschel, Meth. Find. Exp. Clin. Pharmacol., 1993, 13, 205). Microemulsions afford advantages of improved drug solubilization, protection of drug from enzymatic hydrolysis, possible enhancement of drug absorption due to surfactant-induced alterations in membrane fluidity and permeability, ease of preparation, ease of oral administration over solid dosage forms, improved clinical potency, and decreased toxicity (Constantinides et al., Pharmaceutical Research, 1994, 11, 1385; Ho et al., J. Pharm. Sci., 1996, 85, 138-143). Often microemulsions may form spontaneously when their components are brought together at ambient temperature. This may be particularly advantageous when formulating thermolabile drugs, peptides or oligonucleotides. Microemulsions have also been effective in the transdermal delivery of active components in both cosmetic and pharmaceutical applications. It is expected that the microemulsion compositions and formulations of the present invention will facilitate the increased systemic absorption of oligonucleotides and nucleic acids from the gastrointestinal tract, as well as improve the local cellular uptake of oligonucleotides and nucleic acids within the gastrointestinal tract, vagina, buccal cavity and other areas of administration.

[0091] Microemulsions of the present invention may also contain additional components and additives such as sorbitan monostearate (Grill 3), Labrasol, and penetration enhancers to improve the properties of the formulation and to enhance the absorption of the oligohucleotides and nucleic acids of the present invention. Penetration enhancers used in the microemulsions of the present invention may be classified as belonging to one of five broad categories—surfactants, fatty acids, bile salts, chelating agents, and non-chelating non-surfactants (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p. 92). Each of these classes has been discussed above.

[0092] Liposomes

[0093] There are many organized surfactant structures besides microemulsions that have been studied and used for the formulation of drugs. These include monolayers, micelles, bilayers and vesicles. Vesicles, such as liposomes, have attracted great interest because of their specificity and the duration of action they offer from the standpoint of drug delivery. As used in the present invention, the term “liposome” means a vesicle composed of amphiphilic lipids arranged in a spherical bilayer or bilayers.

[0094] Liposomes are unilamellar or multilamellar vesicles which have a membrane formed from a lipophilic material and an aqueous interior. The aqueous portion contains the composition to be delivered. Cationic liposomes possess the advantage of being able to fuse to the cell wall. Non-cationic liposomes, although not able to fuse as efficiently with the cell wall, are taken up by macrophages in vivo.

[0095] In order to cross intact mammalian skin, lipid vesicles must pass through a series of fine pores, each with a diameter less than 50 nm, under the influence of a suitable transdermal gradient. Therefore, it is desirable to use a liposome which is highly deformable and able to pass through such fine pores.

[0096] Further advantages of liposomes include; liposomes obtained from natural phospholipids are biocompatible and biodegradable; liposomes can incorporate a wide range of water and lipid soluble drugs; liposomes can protect encapsulated drugs in their internal compartments from metabolism and degradation (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245). Important considerations in the preparation of liposome formulations are the lipid surface charge, vesicle size and the aqueous volume of the liposomes.

[0097] Liposomes are useful for the transfer and delivery of active ingredients to the site of action. Because the liposomal membrane is structurally similar to biological membranes, when liposomes are applied to a tissue, the liposomes start to merge with the cellular membranes and as the merging of the liposome and cell progresses, the liposomal contents are emptied into the cell where the active agent may act.

[0098] Liposomal formulations have been the focus of extensive investigation as the mode of delivery for many drugs. There is growing evidence that for topical administration, liposomes present several advantages over other formulations. Such advantages include reduced side-effects related to high systemic absorption of the administered drug, increased accumulation of the administered drug at the desired target, and the ability to administer a wide variety of drugs, both hydrophilic and hydrophobic, into the skin.

[0099] Several reports have detailed the ability of liposomes to deliver agents including high-molecular weight DNA into the skin. Compounds including analgesics, antibodies, hormones and high-molecular weight DNAs have been administered to the skin. The majority of applications resulted in the targeting of the upper epidermis.

[0100] Liposomes fall into two broad classes. Cationic liposomes are positively charged liposomes which interact with the negatively charged DNA molecules to form a stable complex. The positively charged DNA/liposome complex binds to the negatively charged cell surface and is internalized in an endosome. Due to the acidic pH within the endosome, the liposomes are ruptured, releasing their contents into the cell cytoplasm (Wang et al., Biochem. Biophys. Res. Commun., 1987, 147, 980-985).

[0101] Liposomes which are pH-sensitive or negatively-charged, entrap DNA rather than complex with it. Since both the DNA and the lipid are similarly charged, repulsion rather than complex formation occurs. Nevertheless, some DNA is entrapped within the aqueous interior of these liposomes. pH-sensitive liposomes have been used to deliver DNA encoding the thymidine kinase gene to cell monolayers in culture. Expression of the exogenous gene was detected in the target cells (Zhou et al., Journal of Controlled Release, 1992, 19, 269-274).

[0102] One major type of liposomal composition includes phospholipids other than naturally-derived phosphatidylcholine. Neutral liposome compositions, for example, can be formed from dimyristoyl phosphatidylcholine (DMPC) or dipalmitoyl phosphatidylcholine (DPPC). Anionic liposome compositions generally are formed from dimyristoyl phosphatidylglycerol, while anionic fusogenic liposomes are formed primarily from dioleoyl phosphatidylethanolamine (DOPE). Another type of liposomal composition is formed from phosphatidylcholine (PC) such as, for example, soybean PC, and egg PC. Another type is formed from mixtures of phospholipid and/or phosphatidylcholine and/or cholesterol.

[0103] Several studies have assessed the topical delivery of liposomal drug formulations to the skin. Application of liposomes containing interferon to guinea pig skin resulted in a reduction of skin herpes sores while delivery of interferon via other means (e.g. as a solution or as an emulsion) were ineffective (Weiner et al., Journal of Drug Targeting, 1992, 2, 405-410). Further, an additional study tested the efficacy of interferon administered as part of a liposomal formulation to the administration of interferon using an aqueous system, and concluded that the liposomal formulation was superior to aqueous administration (du Plessis et al., Antiviral Research, 1992, 18, 259-265).

[0104] Non-ionic liposomal systems have also been examined to determine their utility in the delivery of drugs to the skin, in particular systems comprising non-ionic surfactant and cholesterol. Non-ionic liposomal formulations comprising Novasome™ I (glyceryl dilaurate/cholesterol/polyoxyethylene-10-stearyl ether) and Novasome™ II (glyceryl distearate/cholesterol/polyoxyethylene-10-stearyl ether) were used to deliver cyclosporin-A into the dermis of mouse skin. Results indicated that such non-ionic liposomal systems were effective in facilitating the deposition of cyclosporin-A into different layers of the skin (Hu et al. S.T.P.Pharma. Sci., 1994, 4, 6, 466).

[0105] Liposomes also include “sterically stabilized” liposomes, a term which, as used herein, refers to liposomes comprising one or more specialized lipids that, when incorporated into liposomes, result in enhanced circulation lifetimes relative to liposomes lacking such specialized lipids. Examples of sterically stabilized liposomes are those in which part of the vesicle-forming lipid portion of the liposome (A) comprises one or more glycolipids, such as monosialoganglioside G_(M1), or (B) is derivatized with one or more hydrophilic polymers, such as a polyethylene glycol (PEG) moiety. While not wishing to be bound by any particular theory, it is thought in the art that, at least for sterically stabilized liposomes containing gangliosides, sphingomyelin, or PEG-derivatized lipids, the enhanced circulation half-life of these sterically stabilized liposomes derives from a reduced uptake into cells of the reticuloendothelial system (RES) (Allen et al., FEBS Letters, 1987, 223, 42; Wu et al., Cancer Research, 1993, 53, 3765).

[0106] Various liposomes comprising one or more glycolipids are known in the art. Papahadjopoulos et al. (Ann. N.Y. Acad. Sci., 1987, 507, 64) reported the ability of monosialoganglioside G_(M1), galactocerebroside sulfate and phosphatidylinositol to improve blood half-lives of liposomes. These findings were expounded upon by Gabizon et al. (Proc. Natl. Acad. Sci. U.S.A., 1988, 85, 6949). U.S. Pat. No. 4,837,028 and WO 88/04924, both to Allen et al., disclose liposomes comprising (1) sphingomyelin and (2) the ganglioside G_(M1) or a galactocerebroside sulfate ester. U.S. Pat. No. 5,543,152 (Webb et al.) discloses liposomes comprising sphingomyelin. Liposomes comprising 1,2-sn-dimyristoylphosphatidylcholine are disclosed in Wo 97/13499 (Lim et al.).

[0107] Many liposomes comprising lipids derivatized with one or more hydrophilic polymers, and methods of preparation thereof, are known in the art. Sunamoto et al. (Bull. Chem. Soc. Jpn., 1980, 53, 2778) described liposomes comprising a nonionic detergent, 2C₁₂15G, that contains a PEG moiety. Illum et al. (FEBS Lett., 1984, 167, 79) noted that hydrophilic coating of polystyrene particles with polymeric glycols results in significantly enhanced blood half-lives. Synthetic phospholipids modified by the attachment of carboxylic groups of polyalkylene glycols (e.g., PEG) are described by Sears (U.S. Pat. Nos. 4,426,330 and 4,534,899). Klibanov et al. (FEBS Lett., 1990, 268, 235) described experiments demonstrating that liposomes comprising phosphatidylethanolamine (PE) derivatized with PEG or PEG stearate have significant increases in blood circulation half-lives. Blume et al. (Biochimica et Biophysica Acta, 1990, 1029, 91) extended such observations to other PEG-derivatized phospholipids, e.g., DSPE-PEG, formed from the combination of distearoylphosphatidylethanolamine (DSPE) and PEG. Liposomes having covalently bound PEG moieties on their external surface are described in European Pat. No. EP 0 445 131 B1 and WO 90/04384 to Fisher. Liposome compositions containing 1-20 mole percent of PE derivatized with PEG, and methods of use thereof, are described by Woodle et al. (U.S. Pat. Nos. 5,013,556 and 5,356,633) and Martin et al. (U.S. Pat. No. 5,213,804 and European Pat. No. EP 0 496 813 B1). Liposomes comprising a number of other lipid-polymer conjugates are disclosed in WO 91/05545 and U.S. Pat. No. 5,225,212 (both to Martin et al.) and in WO 94/20073 (Zalipsky et al.) Liposomes comprising PEG-modified ceramide lipids are described in WO 96/10391 (Choi et al.). U.S. Pat. Nos. 5,540,935 (Miyazaki et al.) and 5,556,948 (Tagawa et al.) describe PEG-containing liposomes that can be further derivatized with functional moieties on their surfaces.

[0108] A limited number of liposomes comprising nucleic acids are known in the art. WO 96/40062 to Thierry et al. discloses methods for encapsulating high molecular weight nucleic acids in liposomes. U.S. Pat. No. 5,264,221 to Tagawa et al. discloses protein-bonded liposomes and asserts that the contents of such liposomes may include an antisense RNA. U.S. Pat. No. 5,665,710 to Rahman et al. describes certain methods of encapsulating oligodeoxynucleotides in liposomes. WO 97/04787 to Love et al. discloses liposomes comprising antisense oligonucleotides targeted to the raf gene.

[0109] Transfersomes are yet another type of liposomes, and are highly deformable lipid aggregates which are attractive candidates for drug delivery vehicles. Transfersomes may be described as lipid droplets which are so highly deformable that they are easily able to penetrate through pores which are smaller than the droplet. Transfersomes are adaptable to the environment in which they are used, e.g. they are self-optimizing (adaptive to the shape of pores in the skin), self-repairing, frequently reach their targets without fragmenting, and often self-loading. To make transfersomes it is possible to add surface edge-activators, usually surfactants, to a standard liposomal composition. Transfersomes have been used to deliver serum albumin to the skin The transfersome-mediated delivery of serum albumin has been shown to be as effective as subcutaneous injection of a solution containing serum albumin.

[0110] Surfactants find wide application in formulations such as emulsions (including microemulsions) and liposomes. The most common way of classifying and ranking the properties of the many different types of surfactants, both natural and synthetic, is by the use of the hydrophile/lipophile balance (HLB). The nature of the hydrophilic group (also known as the “head”) provides the most useful means for categorizing the different surfactants used in formulations (Rieger, in Pharmaceutical Dosage Forms, Marcel Dekker, Inc., New York, N.Y., 1988, p. 285).

[0111] If the surfactant molecule is not ionized, it is classified as a nonionic surfactant. Nonionic surfactants find wide application in pharmaceutical and cosmetic products and are usable over a wide range of pH values. In general their HLB values range from 2 to about 18 depending on their structure. Nonionic surfactants include nonionic esters such as ethylene glycol esters, propylene glycol esters, glyceryl esters, polyglyceryl esters, sorbitan esters, sucrose esters, and ethoxylated esters. Nonionic alkanolamides and ethers such as fatty alcohol ethoxylates, propoxylated alcohols, and ethoxylated/propoxylated block polymers are also included in this class. The polyoxyethylene surfactants are the most popular members of the nonionic surfactant class.

[0112] If the surfactant molecule carries a negative charge when it is dissolved or dispersed in water, the surfactant is classified as anionic. Anionic surfactants include carboxylates such as soaps, acyl lactylates, acyl amides of amino acids, esters of sulfuric acid such as alkyl sulfates and ethoxylated alkyl sulfates, sulfonates such as alkyl benzene sulfonates, acyl isethionates, acyl taurates and sulfosuccinates, and phosphates. The most important members of the anionic surfactant class are the alkyl sulfates and the soaps.

[0113] If the surfactant molecule carries a positive charge when it is dissolved or dispersed in water, the surfactant is classified as cationic. Cationic surfactants include quaternary ammonium salts and ethoxylated amines. The quaternary ammonium salts are the most used members of this class.

[0114] If the surfactant molecule has the ability to carry either a positive or negative charge, the surfactant is classified as amphoteric. Amphoteric surfactants include acrylic acid derivatives, substituted alkylamides, N-alkylbetaines and phosphatides.

[0115] The use of surfactants in drug products, formulations and in emulsions has been reviewed (Rieger, in Pharmaceutical Dosage Forms, Marcel Dekker, Inc., New York, N.Y., 1988, p. 285).

[0116] Penetration Enhancers

[0117] In one embodiment, the present invention employs various penetration enhancers to effect the efficient delivery of nucleic acids, particularly oligonucleotides, to the skin of animals. Most drugs are present in solution in both ionized and nonionized forms. However, usually only lipid soluble or lipophilic drugs readily cross cell membranes. It has been discovered that even non-lipophilic drugs may cross cell membranes if the membrane to be crossed is treated with a penetration enhancer. In addition to aiding the diffusion of non-lipophilic drugs across cell membranes, penetration enhancers also enhance the permeability of lipophilic drugs.

[0118] Penetration enhancers may be classified as belonging to one of five broad categories, i.e., surfactants, fatty acids, bile salts, chelating agents, and non-chelating non-surfactants (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p.92). Each of the above mentioned classes of penetration enhancers are described below in greater detail.

[0119] Surfactants: In connection with the present invention, surfactants (or “surface-active agents”) are chemical entities which, when dissolved in an aqueous solution, reduce the surface tension of the solution or the interfacial tension between the aqueous solution and another liquid, with the result that absorption of oligonucleotides through the mucosa is enhanced. In addition to bile salts and fatty acids, these penetration enhancers include, for example, sodium lauryl sulfate, polyoxyethylene-9-lauryl ether and polyoxyethylene-20-cetyl ether) (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p.92); and perfluorochemical emulsions, such as FC-43. Takahashi et al., J. Pharm. Pharmacol., 1988, 40, 252).

[0120] Fatty acids: Various fatty acids and their derivatives which act as penetration enhancers include, for example, oleic acid, lauric acid, capric acid (n-decanoic acid), myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein (1-monooleoyl-rac-glycerol), dilaurin, caprylic acid, arachidonic acid, glycerol 1-monocaprate, 1-dodecylazacycloheptan-2-one, acylcarnitines, acylcholines, C₁₋₁₀ alkyl esters thereof (e.g., methyl, isopropyl and t-butyl), and mono- and di-glycerides thereof (i.e., oleate, laurate, caprate, myristate, palmitate, stearate, linoleate, etc.) (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p.92; Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33; El Hariri et al., J. Pharm. Pharmacol., 1992, 44, 651-654).

[0121] Bile salts: The physiological role of bile includes the facilitation of dispersion and absorption of lipids and fat-soluble vitamins (Brunton, Chapter 38 in: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al. Eds., McGraw-Hill, New York, 1996, pp. 934-935). Various natural bile salts, and their synthetic derivatives, act as penetration enhancers. Thus the term “bile salts” includes any of the naturally occurring components of bile as well as any of their synthetic derivatives. The bile salts of the invention include, for example, cholic acid (or its pharmaceutically acceptable sodium salt, sodium cholate), dehydrocholic acid (sodium dehydrocholate), deoxycholic acid (sodium deoxycholate), glucholic acid (sodium glucholate), glycholic acid (sodium glycocholate), glycodeoxycholic acid (sodium glycodeoxycholate), taurocholic acid (sodium taurocholate), taurodeoxycholic acid (sodium taurodeoxycholate), chenodeoxycholic acid (sodium chenodeoxycholate), ursodeoxycholic acid (UDCA), sodium tauro-24,25-dihydro-fusidate (STDHF), sodium glycodihydrofusidate and polyoxyethylene-9-lauryl ether (POE) (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92; Swinyard, Chapter 39 In: Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990, pages 782-783; Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33; Yamamoto et al., J. Pharm. Exp. Ther., 1992, 263, 25; Yamashita et al., J. Pharm. Sci., 1990, 79, 579-583).

[0122] Chelating Agents: Chelating agents, as used in connection with the present invention, can be defined as compounds that remove metallic ions from solution by forming complexes therewith, with the result that absorption of oligonucleotides through the mucosa is enhanced. With regards to their use as penetration enhancers in the present invention, chelating agents have the added advantage of also serving as DNase inhibitors, as most characterized DNA nucleases require a divalent metal ion for catalysis and are thus inhibited by chelating agents (Jarrett, J. Chromatogr., 1993, 618, 315-339). Chelating agents of the invention include but are not limited to disodium ethylenediaminetetraacetate (EDTA), citric acid, salicylates (e.g., sodium salicylate, 5-methoxysalicylate and homovanilate), N-acyl derivatives of collagen, laureth-9 and N-amino acyl derivatives of beta-diketones (enamines)(Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92; Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33; Buur et al., J. Control Rel., 1990, 14, 43-51).

[0123] Non-chelating non-surfactants: As used herein, non-chelating non-surfactant penetration enhancing compounds can be defined as compounds that demonstrate insignificant activity as chelating agents or as surfactants but that nonetheless enhance absorption of oligonucleotides through the alimentary mucosa (Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33). This class of penetration enhancers include, for example, unsaturated cyclic ureas, 1-alkyl- and 1-alkenylazacyclo-alkanone derivatives (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92); and non-steroidal anti-inflammatory agents such as diclofenac sodium, indomethacin and phenylbutazone (Yamashita et al., J. Pharm. Pharmacol., 1987, 39, 621-626).

[0124] Agents that enhance uptake of oligonucleotides at the cellular level may also be added to the pharmaceutical and other compositions of the present invention. For example, cationic lipids, such as lipofectin (Junichi et al, U.S. Pat. No. 5,705,188), cationic glycerol derivatives, and polycationic molecules, such as polylysine (Lollo et al., PCT Application WO 97/30731), are also known to enhance the cellular uptake of oligonucleotides.

[0125] Other agents may be utilized to enhance the penetration of the administered nucleic acids, including glycols such as ethylene glycol and propylene glycol, pyrrols such as 2-pyrrol, azones, and terpenes such as limonene and menthone.

[0126] Carriers

[0127] Certain compositions of the present invention also incorporate carrier compounds in the formulation. As used herein, “carrier compound” or “carrier” can refer to a nucleic acid, or analog thereof, which is inert (i.e., does not possess biological activity per se) but is recognized as a nucleic acid by in vivo processes that reduce the bioavailability of a nucleic acid having biological activity by, for example, degrading the biologically active nucleic acid or promoting its removal from circulation. The coadministration of a nucleic acid and a carrier compound, typically with an excess of the latter substance, can result in a substantial reduction of the amount of nucleic acid recovered in the liver, kidney or other extracirculatory reservoirs, presumably due to competition between the carrier compound and the nucleic acid for a common receptor. For example, the recovery of a partially phosphorothioate oligonucleotide in hepatic tissue can be reduced when it is coadministered with polyinosinic acid, dextran sulfate, polycytidic acid or 4-acetamido-4′isothiocyano-stilbene-2,2′-disulfonic acid (Miyao et al., Antisense Res. Dev., 1995, 5, 115-121; Takakura et al., Antisense & Nucl. Acid Drug Dev., 1996, 6, 177-183).

[0128] Excipients

[0129] In contrast to a carrier compound, a “pharmaceutical carrier” or “excipient” is a pharmaceutically acceptable solvent, suspending agent or any other pharmacologically inert vehicle for delivering one or more nucleic acids to an animal. The excipient may be liquid or solid and is selected, with the planned manner of administration in mind, so as to provide for the desired bulk, consistency, etc., when combined with a nucleic acid and the other components of a given pharmaceutical composition. Typical pharmaceutical carriers include, but are not limited to, binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose, etc.); fillers (e.g., lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates or calcium hydrogen phosphate, etc.); lubricants (e.g., magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metallic stearates, hydrogenated vegetable oils, corn starch, polyethylene glycols, sodium benzoate, sodium acetate, etc.); disintegrants (e.g., starch, sodium starch glycolate, etc.); and wetting agents (e.g., sodium lauryl sulphate, etc.).

[0130] Pharmaceutically acceptable organic or inorganic excipient suitable for non-parenteral administration which do not deleteriously react with nucleic acids can also be used to formulate the compositions of the present invention. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like.

[0131] Formulations for topical administration of nucleic acids may include sterile and non-sterile aqueous solutions, non-aqueous solutions in common solvents such as alcohols, or solutions of the nucleic acids in liquid or solid oil bases. The solutions may also contain buffers, diluents and other suitable additives. Pharmaceutically acceptable organic or inorganic excipients suitable for non-parenteral administration which do not deleteriously react with nucleic acids can be used.

[0132] Suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like.

[0133] Other Components

[0134] The compositions of the present invention may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels. Thus, for example, the compositions may contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may contain additional materials useful in physically formulating various dosage forms of the compositions of the present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers. However, such materials, when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention. The formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the nucleic acid(s) of the formulation.

[0135] Aqueous suspensions may contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension may also contain stabilizers.

[0136] Certain embodiments of the invention provide pharmaceutical compositions containing (a) one or more antisense compounds and (b) one or more other chemotherapeutic agents which function by a non-antisense mechanism. Examples of such chemotherapeutic agents include but are not limited to daunorubicin, daunomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, esorubicin, bleomycin, mafosfamide, ifosfamide, cytosine, arabinoside, bis-chloroethylnitrosurea, busulfan, mitomycin C, actinomycin D, mithramycin, prednisone, hydroxyprogesterone, testosterone, tamoxifen, dacarbazine, procarbazine, hexamethylmelamine, pentamethylmelamine, mitoxantrone, amsacrine, chlorambucil, methylcyclohexylnitrosurea, nitrogen mustards, melphalan, cyclophosphamide, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-azacytidine, hydroxyurea, deoxycoformycin, 4-hydroxyperoxycyclophosphoramide, 5-fluorouracil (5-FU), 5-fluorodeoxyuridine (5-FUdR), methotrexate (MTX), colchicine, taxol, vincristine, vinblastine, etoposide (VP-16), trimetrexate, irinotecan, topotecan, gemcitabine, teniposide, cisplatin and diethylstilbestrol (DES). See, generally, The Merck Manual of Diagnosis and Therapy, 15th Ed. 1987, pp. 1206-1228, Berkow et al., eds., Rahway, N.J. When used with the compounds of the invention, such chemotherapeutic agents may be used individually (e.g., 5-FU and oligonucleotide), sequentially (e.g., 5-FU and oligonucleotide for a period of time followed by MTX and oligonucleotide), or in combination with one or more other such chemotherapeutic agents (e.g., 5-FU, MTX and oligonucleotide, or 5-FU, radiotherapy and oligonucleotide). Anti-inflammatory drugs, including but not limited to nonsteroidal anti-inflammatory drugs and corticosteroids, and antiviral drugs, including but not limited to ribivirin, vidarabine, acyclovir and ganciclovir, may also be combined in compositions of the invention. See, generally, The Merck Manual of Diagnosis and Therapy, 15th Ed., Berkow et al., eds., 1987, Rahway, N.J., pages 2499-2506 and 46-49, respectively). Other non-antisense chemotherapeutic agents are also within the scope of this invention. Two or more combined compounds may be used together or sequentially.

[0137] In another related embodiment, compositions of the invention may contain one or more antisense compounds, particularly oligonucleotides, targeted to a first nucleic acid and one or more additional antisense compounds targeted to a second nucleic acid target. Numerous examples of antisense compounds are known in the art. Two or more combined compounds may be used together or sequentially.

[0138] The formulation of therapeutic compositions and their subsequent administration is believed to be within the skill of those in the art. Dosing is dependent on severity and responsiveness of the disease state to be treated, with the course of treatment lasting from several days to several months, or until a cure is effected or a diminution of the disease state is achieved. Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. Optimum dosages may vary depending on the relative potency of individual oligonucleotides, and can generally be estimated based on EC₅₀s found to be effective in in vi tro and in vivo animal models. In general, dosage is from 0.01 ug to 100 g per kg of body weight, and may be given once or more daily, weekly, monthly or yearly, or even once every 2 to 20 years. Persons of ordinary skill in the art can easily estimate repetition rates for dosing based on measured residence times and concentrations of the drug in bodily fluids or tissues. Following successful treatment, it may be desirable to have the patient undergo maintenance therapy to prevent the recurrence of the disease state, wherein the oligonucleotide is administered in maintenance doses, ranging from 0.01 ug to 100 g per kg of body weight, once or more daily, to once every 20 years.

[0139] While the present invention has been described with specificity in accordance with certain of its preferred embodiments, the following examples serve only to illustrate the invention and are not intended to limit the same.

EXAMPLES Example 1

[0140] Nucleoside Phosphoramidites for Oligonucleotide Synthesis Deoxy and 2′-alkoxy amidites

[0141] 2′-Deoxy and 2′-methoxy beta-cyanoethyldiisopropyl phosphoramidites were purchased from commercial sources (e.g. Chemgenes, Needham Mass. or Glen Research, Inc. Sterling Va.). Other 2′-O-alkoxy substituted nucleoside amidites are prepared as described in U.S. Pat. No. 5,506,351, herein incorporated by reference. For oligonucleotides synthesized using 2′-alkoxy amidites, optimized synthesis cycles were developed that incorporate multiple steps coupling longer wait times relative to standard synthesis cycles.

[0142] The following abbreviations are used in the text: thin layer chromatography (TLC), melting point (MP), high pressure liquid chromatography (HPLC), Nuclear Magnetic Resonance (NMR), argon (Ar), methanol (MeOH), dichloromethane (CH₂Cl₂), triethylamine (TEA), dimethyl formamide (DMF), ethyl acetate (EtOAc), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF).

[0143] Oligonucleotides containing 5-methyl-2′-deoxycytidine (5-Me-dC) nucleotides were synthesized according to published methods (Sanghvi, et. al., Nucleic Acids Research, 1993, 21, 3197-3203) using commercially available phosphoramidites (Glen Research, Sterling Va. or ChemGenes, Needham Mass.) or prepared as follows:

[0144] Preparation of 5′-O-Dimethoxytrityl-thymidine Intermediate for 5-methyl dC amidite

[0145] To a 50 L glass reactor equipped with air stirrer and Ar gas line was added thymidine (1.00 kg, 4.13 mol) in anhydrous pyridine (6 L) at ambient temperature. Dimethoxytrityl (DMT) chloride (1.47 kg, 4.34 mol, 1.05 eq) was added as a solid in four portions over 1 h. After 30 min, TLC indicated approx. 95% product, 2% thymidine, 5% DMT reagent and by-products and 2 % 3′,5′-bis DMT product (Rf in EtOAc 0.45, 0.05, 0.98, 0.95 respectively). Saturated sodium bicarbonate (4 L) and CH₂Cl₂ were added with stirring (pH of the aqueous layer 7.5). An additional 18 L of water was added, the mixture was stirred, the phases were separated, and the organic layer was transferred to a second 50 L vessel. The aqueous layer was extracted with additional CH₂Cl₂ (2×2 L). The combined organic layer was washed with water (10 L) and then concentrated in a rotary evaporator to approx. 3.6 kg total weight. This was redissolved in CH₂Cl₂ (3.5 L), added to the reactor followed by water (6 L) and hexanes (13 L). The mixture was vigorously stirred and seeded to give a fine white suspended solid starting at the interface. After stirring for 1 h, the suspension was removed by suction through a ½″ diameter teflon tube into a 20 L suction flask, poured onto a 25 cm Coors Buchner funnel, washed with water (2×3 L) and a mixture of hexanes-CH₂Cl₂ (4:1, 2×3 L) and allowed to air dry overnight in pans (1″ deep). This was further dried in a vacuum oven (75° C., 0.1 mm Hg, 48 h) to a constant weight of 2072 g (93%) of a white solid, (mp 122-124° C.). TLC indicated a trace contamination of the bis DMT product. NMR spectroscopy also indicated that 1-2 mole percent pyridine and about 5 mole percent of hexanes was still present.

[0146] Preparation of 5′-O-Dimethoxytrityl-2′-deoxy-5-methylcytidine Intermediate for 5-methyl-dC amidite

[0147] To a 50 L Schott glass-lined steel reactor equipped with an electric stirrer, reagent addition pump (connected to an addition funnel), heating/cooling system, internal thermometer and an Ar gas line was added 5′-O-dimethoxytrityl-thymidine (3.00 kg, 5.51 mol), anhydrous acetonitrile (25 L) and TEA (12.3 L, 88.4 mol, 16 eq). The mixture was chilled with stirring to −10° C. internal temperature (external −20° C.). Trimethylsilylchloride (2.1 L, 16.5 mol, 3.0 eq) was added over 30 minutes while maintaining the internal temperature below −5° C., followed by a wash of anhydrous acetonitrile (1 L). Note: the reaction is mildly exothermic and copious hydrochloric acid fumes form over the course of the addition. The reaction was allowed to warm to 0° C. and the reaction progress was confirmed by TLC (EtOAc-hexanes 4:1; R_(f) 0.43 to 0.84 of starting material and silyl product, respectively). Upon completion, triazole (3.05 kg, 44 mol, 8.0 eq) was added the reaction was cooled to −20° C. internal temperature (external −30° C.). Phosphorous oxychloride (1035 mL, 11.1 mol, 2.01 eq) was added over 60 min so as to maintain the temperature between −20° C. and −10° C. during the strongly exothermic process, followed by a wash of anhydrous acetonitrile (1 L). The reaction was warmed to 0° C. and stirred for 1 h. TLC indicated a complete conversion to the triazole product (R_(f) 0.83 to 0.34 with the product spot glowing in long wavelength UV light). The reaction mixture was a peach-colored thick suspension, which turned darker red upon warming without apparent decomposition. The reaction was cooled to −15° C. internal temperature and water (5 L) was slowly added at a rate to maintain the temperature below +10° C. in order to quench the reaction and to form a homogenous solution. (Caution: this reaction is initially very strongly exothermic). Approximately one-half of the reaction volume (22 L) was transferred by air pump to another vessel, diluted with EtOAc (12 L) and extracted with water (2×8 L). The combined water layers were back-extracted with EtOAc (6 L). The water layer was discarded and the organic layers were concentrated in a 20 L rotary evaporator to an oily foam. The foam was coevaporated with anhydrous acetonitrile (4 L) to remove EtOAc. (note: dioxane may be used instead of anhydrous acetonitrile if dried to a hard foam). The second half of the reaction was treated in the same way. Each residue was dissolved in dioxane (3 L) and concentrated ammonium hydroxide (750 mL) was added. A homogenous solution formed in a few minutes and the reaction was allowed to stand overnight (although the reaction is complete within 1 h).

[0148] TLC indicated a complete reaction (product R_(f) 0.35 in EtOAc-MeOH 4:1). The reaction solution was concentrated on a rotary evaporator to a dense foam. Each foam was slowly redissolved in warm EtOAc (4 L; 50° C.), combined in a 50 L glass reactor vessel, and extracted with water (2×4L) to remove the triazole by-product. The water was back-extracted with EtOAc (2 L). The organic layers were combined and concentrated to about 8 kg total weight, cooled to 0° C. and seeded with crystalline product. After 24 hours, the first crop was collected on a 25 cm Coors Buchner funnel and washed repeatedly with EtOAc (3×3L) until a white powder was left and then washed with ethyl ether (2×3L). The solid was put in pans (1″ deep) and allowed to air dry overnight. The filtrate was concentrated to an oil, then redissolved in EtOAc (2 L), cooled and seeded as before. The second crop was collected and washed as before (with proportional solvents) and the filtrate was first extracted with water (2×1L) and then concentrated to an oil. The residue was dissolved in EtOAc (1 L) and yielded a third crop which was treated as above except that more washing was required to remove a yellow oily layer.

[0149] After air-drying, the three crops were dried in a vacuum oven (50° C., 0.1 mm Hg, 24 h) to a constant weight (1750, 600 and 200 g, respectively) and combined to afford 2550 g (85%) of a white crystalline product (MP 215-217° C.) when TLC and NMR spectroscopy indicated purity. The mother liquor still contained mostly product (as determined by TLC) and a small amount of triazole (as determined by NMR spectroscopy), bis DMT product and unidentified minor impurities. If desired, the mother liquor can be purified by silica gel chromatography using a gradient of MeOH (0-25%) in EtOAc to further increase the yield.

[0150] Preparation of 5′-O-Dimethoxytrityl-2′-deoxy-N4-benzoyl-5-methylcytidine Penultimate Intermediate for 5-methyl dC amidite

[0151] Crystalline 5′ -O-dimethoxytrityl-5-methyl-2 ′-deoxycytidine (2000 g, 3.68 mol) was dissolved in anhydrous DMF (6.0 kg) at ambient temperature in a 50 L glass reactor vessel equipped with an air stirrer and argon line. Benzoic anhydride (Chem Impex not Aldrich, 874 g, 3.86 mol, 1.05 eq) was added and the reaction was stirred at ambient temperature for 8 h. TLC (CH₂Cl₂-EtOAc; CH₂Cl₂-EtOAc 4:1; R_(f) 0.25) indicated approx. 92% complete reaction. An additional amount of benzoic anhydride (44 g, 0.19 mol) was added. After a total of 18 h, TLC indicated approx. 96% reaction completion. The solution was diluted with EtOAc (20 L), TEA (1020 mL, 7.36 mol, ca 2.0 eq) was added with stirring, and the mixture was extracted with water (15 L, then 2×10 L). The aqueous layer was removed (no back-extraction was needed) and the organic layer was concentrated in 2×20 L rotary evaporator flasks until a foam began to form. The residues were coevaporated with acetonitrile (1.5 L each) and dried (0.1 mm Hg, 25° C., 24 h) to 2520 g of a dense foam. High pressure liquid chromatography (HPLC) revealed a contamination of 6.3% of N4, 3′-O-dibenzoyl product, but very little other impurities.

[0152] The product was purified by Biotage column chromatography (5 kg Biotage) prepared with 65:35:1 hexanes-EtOAc-TEA (4L). The crude product (800 g),dissolved in CH₂Cl₂ (2 L), was applied to the column. The column was washed with the 65:35:1 solvent mixture (20 kg), then 20:80:1 solvent mixture (10 kg), then 99:1 EtOAc:TEA (17kg). The fractions containing the product were collected, and any fractions containing the product and impurities were retained to be resubjected to column chromatography. The column was re-equilibrated with the original 65:35:1 solvent mixture (17 kg). A second batch of crude product (840 g) was applied to the column as before. The column was washed with the following solvent gradients: 65:35:1 (9 kg), 55:45:1 (20 kg), 20:80:1 (10 kg), and 99:1 EtOAc:TEA(15 kg). The column was reequilibrated as above, and a third batch of the crude product (850 g) plus impure fractions recycled from the two previous columns (28 g) was purified following the procedure for the second batch. The fractions containing pure product combined and concentrated on a 20L rotary evaporator, co-evaporated with acetontirile (3 L) and dried (0.1 mm Hg, 48 h, 25° C.) to a constant weight of 2023 g (85%) of white foam and 20 g of slightly contaminated product from the third run. HPLC indicated a purity of 99.8% with the balance as the diBenzoyl product.

[0153] [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-deoxy-N⁴-benzoyl-5-methylcytidin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (5-methyl dC amidite)

[0154] 5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-deoxy-N⁴-benzoyl-5-methylcytidine (998 g, 1.5 mol) was dissolved in anhydrous DMF (2 L). The solution was co-evaporated with toluene (300 ml) at 50° C. under reduced pressure, then cooled to room temperature and 2-cyanoethyl tetraisopropylphosphorodiamidite (680 g, 2.26 mol) and tetrazole (52.5 g, 0.75 mol) were added. The mixture was shaken until all tetrazole was dissolved, N-methylimidazole (15 ml) was added and the mixture was left at room temperature for 5 hours. TEA (300 ml) was added, the mixture was diluted with DMF (2.5 L) and water (600 ml), and extracted with hexane (3×3 L). The mixture was diluted with water (1.2 L) and extracted with a mixture of toluene (7.5 L) and hexane (6 L). The two layers were separated, the upper layer was washed with DMF-water (7:3 v/v, 3×2 L) and water (3×2 L), and the phases were separated. The organic layer was dried (Na₂SO₄), filtered and rotary evaporated. The residue was co-evaporated with acetonitrile (2×2 L) under reduced pressure and dried to a constant weight (25° C., 0.1 mm Hg, 40 h) to afford 1250 g an off-white foam solid (96%).

[0155] 2′-Fluoro amidites

[0156] 2′-Fluorodeoxyadenosine amidites

[0157] 2′-fluoro oligonucleotides were synthesized as described previously [Kawasaki, et. al., J. Med. Chem., 1993, 36, 831-841] and U.S. Pat. No. 5,670,633, herein incorporated by reference. The preparation of 2′-fluoropyrimidines containing a 5-methyl substitution are described in U.S. Pat. No. 5,861,493. Briefly, the protected nucleoside N6-benzoly-2′-deoxy-2′-fluoroadenosine was synthesized utilizing commercially available 9-beta-D-arabinofuranosyladenine as starting material and whereby the 2′-alpha-fluoro atom is introduced by a S_(N)2-displacement of a 2′-beta-triflate group. Thus N6-benzoyl-9-beta-D-arabinofuranosyladenine was selectively protected in moderate yield as the 3′,5′-ditetrahydropyranyl (THP) intermediate. Deprotection of the THP and N6-benzoyl groups was accomplished using standard methodologies to obtain the 5′-dimethoxytrityl-(DMT) and 5′-DMT-3′-phosphoramidite intermediates.

[0158] 2′-Fluorodeoxyguanosine

[0159] The synthesis of 2′-deoxy-2′-fluoroguanosine was accomplished using tetraisopropyldisiloxanyl (TPDS) protected 9-beta-D-arabinofuranosylguanine as starting material, and conversion to the intermediate isobutyryl-arabinofuranosylguanosine. Alternatively, isobutyryl-arabinofuranosylguanosine was prepared as described by Ross et al., (Nucleosides & Nucleosides, 16, 1645, 1997). Deprotection of the TPDS group was followed by protection of the hydroxyl group with THP to give isobutyryl di-THP protected arabinofuranosylguanine. Selective O-deacylation and triflation was followed by treatment of the crude product with fluoride, then deprotection of the THP groups. Standard methodologies were used to obtain the 5′-DMT- and 5′-DMT-3′-phosphoramidites.

[0160] 2′-Fluorouridine

[0161] Synthesis of 2′-deoxy-2′-fluorouridine was accomplished by the modification of a literature procedure in which 2,2′-anhydro-1-beta-D-arabinofuranosyluracil was treated with 70% hydrogen fluoride-pyridine. Standard procedures were used to obtain the 5′-DMT and 5′-DMT-3′phosphoramidites.

[0162] 2′-Fluorodeoxycytidine

[0163] 2′-deoxy-2′-fluorocytidine was synthesized via amination of 2′-deoxy-2′-fluorouridine, followed by selective protection to give N4-benzoyl-2′-deoxy-2′-fluorocytidine. Standard procedures were used to obtain the 5′-DMT and 5′-DMT-3 ′phosphoramidites.

[0164] 2′-0-(2-Methoxyethyl) Modified amidites

[0165] 2′-O-Methoxyethyl-substituted nucleoside amidites (otherwise known as MOE amidites) are prepared as follows, or alternatively, as per the methods of Martin, P., (Helvetica Chimica Acta, 1995, 78, 486-504).

[0166] Preparation of 2′-O-(2-methoxyethyl)-5-methyluridine Intermediate

[0167] 2,2′-Anhydro-5-methyl-uridine (2000 g, 8.32 mol), tris(2-methoxyethyl)borate (2504 g, 10.60 mol), sodium bicarbonate (60 g, 0.70 mol) and anhydrous 2-methoxyethanol (5 L) were combined in a 12 L three necked flask and heated to 130° C. (internal temp) at atmospheric pressure, under an argon atmosphere with stirring for 21 h. TLC indicated a complete reaction. The solvent was removed under reduced pressure until a sticky gum formed (50-85° C. bath temp and 100-11 mm Hg) and the residue was redissolved in water (3 L) and heated to boiling for 30 min in order the hydrolyze the borate esters. The water was removed under reduced pressure until a foam began to form and then the process was repeated. HPLC indicated about 77% product, 15% dimer (5′ of product attached to 2′ of starting material) and unknown derivatives, and the balance was a single unresolved early eluting peak.

[0168] The gum was redissolved in brine (3 L), and the flask was rinsed with additional brine (3 L). The combined aqueous solutions were extracted with chloroform (20 L) in a heavier-than continuous extractor for 70 h. The chloroform layer was concentrated by rotary evaporation in a 20 L flask to a sticky foam (2400 g). This was coevaporated with MeOH (400 mL) and EtOAc (8 L) at 75° C. and 0.65 atm until the foam dissolved at which point the vacuum was lowered to about 0.5 atm. After 2.5 L of distillate was collected a precipitate began to form and the flask was removed from the rotary evaporator and stirred until the suspension reached ambient temperature. EtOAc (2 L) was added and the slurry was filtered on a 25 cm table top Buchner funnel and the product was washed with EtOAc (3×2 L). The bright white solid was air dried in pans for 24 h then further dried in a vacuum oven (50° C., 0.1 mm Hg, 24 h) to afford 1649 g of a white crystalline solid (mp 115.5-116.5° C.).

[0169] The brine layer in the 20 L continuous extractor was further extracted for 72 h with recycled chloroform. The chloroform was concentrated to 120 g of oil and this was combined with the mother liquor from the above filtration (225 g), dissolved in brine (250 mL) and extracted once with chloroform (250 mL). The brine solution was continuously extracted and the product was crystallized as described above to afford an additional 178 g of crystalline product containing about 2% of thymine. The combined yield was 1827 g (69.4%). HPLC indicated about 99.5% purity with the balance being the dimer.

[0170] Preparation of 5′-O-DMT-2′-O-(2-methoxyethyl)-5-methyluridine Penultimate Intermediate

[0171] In a 50 L glass-lined steel reactor, 2′-O-(2-methoxyethyl)-5-methyl-uridine (MOE-T, 1500 g, 4.738 mol), lutidine (1015 g, 9.476 mol) were dissolved in anhydrous acetonitrile (15 L). The solution was stirred rapidly and chilled to −10° C. (internal temperature). Dimethoxytriphenylmethyl chloride (1765.7 g, 5.21 mol) was added as a solid in one portion. The reaction was allowed to warm to −2° C. over 1 h. (Note: The reaction was monitored closely by TLC (EtOAc) to determine when to stop the reaction so as to not generate the undesired bis-DMT substituted side product). The reaction was allowed to warm from −2 to 3° C. over 25 min. then quenched by adding MeOH (300 mL) followed after 10 min by toluene (16 L) and,water (16 L). The solution was transferred to a clear 50 L vessel with a bottom outlet, vigorously stirred for 1 minute, and the layers separated. The aqueous layer was removed and the organic layer was washed successively with 10% aqueous citric acid (8 L) and water (12 L). The product was then extracted into the aqueous phase by washing the toluene solution with aqueous sodium hydroxide (0.5N, 16 L and 8 L). The combined aqueous layer was overlayed with toluene (12 L) and solid citric acid (8 moles, 1270 g) was added with vigorous stirring to lower the pH of the aqueous layer to 5.5 and extract the product into the toluene. The organic layer was washed with water (10 L) and TLC of the organic layer indicated a trace of DMT-O-Me, bis DMT and dimer DMT.

[0172] The toluene solution was applied to a silica gel column (6 L sintered glass funnel containing approx. 2 kg of silica gel slurried with toluene (2 L) and TEA(25 mL)) and the fractions were eluted with toluene (12 L) and EtOAc (3×4 L) using vacuum applied to a filter flask placed below the column. The first EtOAc fraction containing both the desired product and impurities were resubjected to column chromatography as above. The clean fractions were combined, rotary evaporated to a foam, coevaporated with acetonitrile (6 L) and dried in a vacuum oven (0.1 mm Hg, 40 h, 40° C.) to afford 2850 g of a white crisp foam. NMR spectroscopy indicated a 0.25 mole % remainder of acetonitrile (calculates to be approx. 47 g) to give a true dry weight of 2803 g (96%). HPLC indicated that the product was 99.41% pure, with the remainder being 0.06 DMT-O-Me, 0.10 unknown, 0.44 bis DMT, and no detectable dimer DMT or 3′-O-DMT.

[0173] Preparation of [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O(2-methoxyethyl)-5-methyluridin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE T amidite)

[0174] 5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-5-methyluridine (1237 g, 2.0 mol) was dissolved in anhydrous DMF (2.5 L). The solution was co-evaporated with toluene (200 ml) at 50° C. under reduced pressure, then cooled to room temperature and 2-cyanoethyl tetraisopropylphosphorodiamidite (900 g, 3.0 mol) and tetrazole (70 g, 1.0 mol) were added. The mixture was shaken until all tetrazole was dissolved, N-methylimidazole (20 ml) was added and the solution was left at room temperature for 5 hours. TEA (300 ml) was added, the mixture was diluted with DMF (3.5 L) and water (600 ml) and extracted with hexane (3×3L). The mixture was diluted with water (1.6 L) and extracted with the mixture of toluene (12 L) and hexanes (9 L). The upper layer was washed with DMF-water (7:3 v/v, 3×3 L) and water (3×3 L). The organic layer was dried (Na₂SO₄), filtered and evaporated. The residue was co-evaporated with acetonitrile (2×2 L) under reduced pressure and dried in a vacuum oven (25° C., 0.1 mm Hg, 40 h) to afford 1526 g of an off-white foamy solid (95%).

[0175] Preparation of 5′-O-Dimethoxytrityl-2′-O-(2-methoxyethyl)-5-methylcytidine Intermediate

[0176] To a 50 L Schott glass-lined steel reactor equipped with an electric stirrer, reagent addition pump (connected to an addition funnel), heating/cooling system, internal thermometer and argon gas line was added 5′-O-dimethoxytrityl-2′-O-(2-methoxyethyl)-5-methyl-uridine (2.616 kg, 4.23 mol, purified by base extraction only and no scrub column), anhydrous acetonitrile (20 L), and TEA (9.5 L, 67.7 mol, 16 eq). The mixture was chilled with stirring to −10° C. internal temperature (external −20° C.). Trimethylsilylchloride (1.60 L, 12.7 mol, 3.0 eq) was added over 30 min. while maintaining the internal temperature below −5° C., followed by a wash of anhydrous acetonitrile (1 L). (Note: the reaction is mildly exothermic and copious hydrochloric acid fumes form over the course of the addition). The reaction was allowed to warm to 0° C. and the reaction progress was confirmed by TLC (EtOAc, R_(f) 0.68 and 0.87 for starting material and silyl product, respectively). Upon completion, triazole (2.34 kg, 33.8 mol, 8.0 eq) was added the reaction was cooled to −20° C. internal temperature (external −30° C.). Phosphorous oxychloride (793 mL, 8.51 mol, 2.01 eq) was added slowly over 60 min so as to maintain the temperature between −20° C. and −10° C. (note: strongly exothermic), followed by a wash of anhydrous acetonitrile (1 L). The reaction was warmed to 0° C. and stirred for 1 h, at which point it was an off-white thick suspension. TLC indicated a complete conversion to the triazole product (EtOAc, R_(f) 0.87 to 0.75 with the product spot glowing in long wavelength UV light). The reaction was cooled to −15° C. and water (5 L) was slowly added at a rate to maintain the temperature below +10° C. in order to quench the reaction and to form a homogenous solution. (Caution: this reaction is initially very strongly exothermic). Approximately one-half of the reaction volume (22 L) was transferred by air pump to another vessel, diluted with EtOAc (12 L) and extracted with water (2×8 L). The second half of the reaction was treated in the same way. The combined aqueous layers were back-extracted with EtOAc (8 L) The organic layers were combined and concentrated in a 20 L rotary evaporator to an oily foam. The foam was coevaporated with anhydrous acetonitrile (4 L) to remove EtOAc. (note: dioxane may be used instead of anhydrous acetonitrile if dried to a hard foam). The residue was dissolved in dioxane (2 L) and concentrated ammonium hydroxide (750 mL) was added. A homogenous solution formed in a few minutes and the reaction was allowed to stand overnight.

[0177] TLC indicated a complete reaction (CH₂Cl₂-acetone-MeOH, 20:5:3, R_(f) 0.51). The reaction solution was concentrated on a rotary evaporator to a dense foam and slowly redissolved in warm CH₂Cl₂ (4 L, 40° C.) and transferred to a 20 L glass extraction vessel equipped with a air-powered stirrer. The organic layer was extracted with water (2×6 L) to remove the triazole by-product. (Note: In the first extraction an emulsion formed which took about 2 h to resolve). The water layer was back-extracted with CH₂Cl₂ (2×2 L), which in turn was washed with water (3 L). The combined organic layer was concentrated in 2×20 L flasks to a gum and then recrystallized from EtOAc seeded with crystalline product. After sitting overnight, the first crop was collected on a 25 cm Coors Buchner funnel and washed repeatedly with EtOAc until a white free-flowing powder was left (about 3×3 L). The filtrate was concentrated to an oil recrystallized from EtOAc, and collected as above. The solid was air-dried in pans for 48 h, then further dried in a vacuum oven (50° C., 0.1 mm Hg, 17 h) to afford 2248 g of a bright white, dense solid (86%). An HPLC analysis indicated both crops to be 99.4% pure and NMR spectroscopy indicated only a faint trace of EtOAc remained.

[0178] Preparation of 5′-O-dimethoxytrityl-2′-O-(2-methoxyethyl)-N4-benzoyl-5-methyl-cytidine Penultimate Intermediate:

[0179] Crystalline 5′-O-dimethoxytrityl-2′-O-(2-methoxyethyl)-5-methyl-cytidine (1000 g, 1.62 mol) was suspended in anhydrous DMF (3 kg) at ambient temperature and stirred under an Ar atmosphere. Benzoic anhydride (439.3 g, 1.94 mol) was added in one portion. The solution clarified after 5 hours and was stirred for 16 h. HPLC indicated 0.45% starting material remained (as well as 0.32% N4, 3′-O-bis Benzoyl). An additional amount of benzoic anhydride (6.0 g, 0.0265 mol) was added and after 17 h, HPLC indicated no starting material was present. TEA (450 mL, 3.24 mol) and toluene (6 L) were added with stirring for 1 minute. The solution was washed with water (4×4 L), and brine (2×4 L). The organic layer was partially evaporated on a 20 L rotary evaporator to remove 4 L of toluene and traces of water. HPLC indicated that the bis benzoyl side product was present as a 6% impurity. The residue was diluted with toluene (7 L) and anhydrous DMSO (200 mL, 2.82 mol) and sodium hydride (60% in oil, 70 g, 1.75 mol) was added in one portion with stirring at ambient temperature over 1 h. The reaction was quenched by slowly adding then washing with aqueous citric acid (10%, 100 mL over 10 min, then 2×4 L), followed by aqueous sodium bicarbonate (2%, 2 L), water (2×4 L) and brine (4 L). The organic layer was concentrated on a 20 L rotary evaporator to about 2 L total volume. The residue was purified by silica gel column chromatography (6 L Buchner funnel containing 1.5 kg of silica gel wetted with a solution of EtOAc-hexanes-TEA(70:29:1)). The product was eluted with the same solvent (30 L) followed by straight EtOAc (6 L). The fractions containing the product were combined, concentrated on a rotary evaporator to a foam and then dried in a vacuum oven (50° C., 0.2 mm Hg, 8 h) to afford 1155 g of a crisp, white foam (98%). HPLC indicated a purity of >99.7%.

[0180] Preparation of [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N⁴-benzoyl-5-methylcytidin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE 5-Me-C amidite)

[0181] 5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N⁴-benzoyl-5-methylcytidine (1082 g, 1.5 mol) was dissolved in anhydrous DMF (2 L) and co-evaporated with toluene (300 ml) at 50° C. under reduced pressure. The mixture was cooled to room temperature and 2-cyanoethyl tetraisopropylphosphorodiamidite (680 g, 2.26 mol) and tetrazole (52.5 g, 0.75 mol) were added. The mixture was shaken until all tetrazole was dissolved, N-methylimidazole (30 ml) was added, and the mixture was left at room temperature for 5 hours. TEA (300 ml) was added, the mixture was diluted with DMF (1 L) and water (400 ml) and extracted with hexane (3×3 L). The mixture was diluted with water (1.2 L) and extracted with a mixture of toluene (9 L) and hexanes (6 L). The two layers were separated and the upper layer was washed with DMF-water (60:40 v/v, 3×3 L) and water (3×2 L). The organic layer was dried (Na₂SO₄), filtered and evaporated. The residue was co-evaporated with acetonitrile (2×2 L) under reduced pressure and dried in a vacuum oven (25 ° C., 0.1 mm Hg, 40 h) to afford 1336 g of an off-white foam (97%).

[0182] Preparation of [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N⁶-benzoyladenosin-3′-0-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE A amdite)

[0183] 5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N⁶-benzoyladenosine (purchased from Reliable Biopharmaceutical, St. Lois, Mo.), 1098 g, 1.5 mol) was dissolved in anhydrous DMF (3 L) and co-evaporated with toluene (300 ml) at 50° C. The mixture was cooled to room temperature and 2-cyanoethyl tetraisopropylphosphorodiamidite (680 g, 2.26 mol) and tetrazole (78.8 g, 1.24 mol) were added. The mixture was shaken until all tetrazole was dissolved, N-methylimidazole (30 ml) was added, and mixture was left at room temperature for 5 hours. TEA (300 ml) was added, the mixture was diluted with DMF (1 L) and water (400 ml) and extracted with hexanes (3×3 L). The mixture was diluted with water (1.4 L) and extracted with the mixture of toluene (9 L) and hexanes (6 L). The two layers were separated and the upper layer was washed with DMF-water (60:40, v/v, 3×3 L) and water (3×2 L). The organic layer was dried (Na₂SO₄), filtered and evaporated to a sticky foam. The residue was co-evaporated with acetonitrile (2.5 L) under reduced pressure and dried in a vacuum oven (25° C., 0.1 mm Hg, 40 h) to afford 1350 g of an off-white foam solid (96%).

[0184] Prepartion of [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N⁴-isobutyrylguanosin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE G amidite)

[0185] 5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N⁴-isobutyrlguanosine (purchased from Reliable Biopharmaceutical, St. Louis, Mo., 1426 g, 2.0 mol) was dissolved in anhydrous DMF (2 L). The solution was co-evaporated with toluene (200 ml) at 50° C., cooled to room temperature and 2-cyanoethyl tetraisopropylphosphorodiamidite (900 g, 3.0 mol) and tetrazole (68 g, 0.97 mol) were added. The mixture was shaken until all tetrazole was dissolved, N-methylimidazole (30 ml) was added, and the mixture was left at room temperature for 5 hours. TEA (300 ml) was added, the mixture was diluted with DMF (2 L) and water (600 ml) and extracted with hexanes (3×3 L). The mixture was diluted with water (2 L) and extracted with a mixture of toluene (10 L) and hexanes (5 L). The two layers were separated and the upper layer was washed with DMF-water (60:40, v/v, 3×3 L). EtOAc (4 L) was added and the solution was washed with water (3×4 L). The organic layer was dried (Na₂SO₄), filtered and evaporated to approx. 4 kg. Hexane (4 L) was added, the mixture was shaken for 10 min, and the supernatant liquid was decanted. The residue was co-evaporated with acetonitrile (2×2 L) under reduced pressure and dried in a vacuum oven (25° C., 0.1 mm Hg, 40 h) to afford 1660 g of an off-white foamy solid (91%).

[0186] 2′-O-(Aminooxyethyl)nucleoside amidites and 2′-O-(dimethylaminooxyethyl)nucleoside amidites

[0187] 2′-(Dimethylaminooxyethoxy)nucleoside amidites

[0188] 2′-(Dimethylaminooxyethoxy)nucleoside amidites (also known in the art as 2′-O-(dimethylaminooxyethyl)nucleoside amidites) are prepared as described in the following paragraphs. Adenosine, cytidine and guanosine nucleoside amidites are prepared similarly to the thymidine (5-methyluridine) except the exocyclic amines are protected with a benzoyl moiety in the case of adenosine and cytidine and with isobutyryl in the case of guanosine.

[0189] 5′-O-tert-Butyldiphenylsilyl-O²-2′-anhydro-5-methyluridine

[0190] O²-2′-anhydro-5-methyluridine (Pro. Bio. Sint., Varese, Italy, 100.0 g, 0.416 mmol), dimethylaminopyridine (0.66 g, 0.013 eq, 0.0054 mmol) were dissolved in dry pyridine (500 ml) at ambient temperature under an argon atmosphere and with mechanical stirring. tert-Butyldiphenylchlorosilane (125.8 g, 119.0 mL, 1.1 eq, 0.458 mmol) was added in one portion. The reaction was stirred for 16 h at ambient temperature. TLC (R_(f) 0.22, EtOAc) indicated a complete reaction. The solution was concentrated under reduced pressure to a thick oil. This was partitioned between CH₂Cl₂ (1 L) and saturated sodium bicarbonate (2×1 L) and brine (1 L). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to a thick oil. The oil was dissolved in a 1:1 mixture of EtOAc and ethyl ether (600 mL) and cooling the solution to −10° C. afforded a white crystalline solid which was collected by filtration, washed with ethyl ether (3 ×2 00 mL) and dried (40° C., 1 mm Hg, 24 h) to afford 149 g of white solid (74.8%). TLC and NMR spectroscopy were consistent with pure product.

[0191] 5′-O-tert-Butyldiphenylsilyl-2′-O-(2-hydroxyethyl)-5-methyluridine

[0192] In the fume hood, ethylene glycol (350 mL, excess) was added cautiously with manual stirring to a 2 L stainless steel pressure reactor containing borane in tetrahydrofuran (1.0 M, 2.0 eq, 622 mL). (Caution : evolves hydrogen gas). 5′-O-tert-Butyldiphenylsilyl-O²-2′-anhydro-5-methyluridine (149 g, 0.311 mol) and sodium bicarbonate (0.074 g, 0.003 eq) were added with manual stirring. The reactor was sealed and heated in an oil bath until an internal temperature of 160° C. was reached and then maintained for 16 h (pressure<100 psig). The reaction vessel was cooled to ambient temperature and opened. TLC (EtOAc, R_(f) 0.67 for desired product and R_(f) 0.82 for ara-T side product) indicated about 70% conversion to the product. The solution was concentrated under reduced pressure (10 to 1 mm Hg) in a warm water bath (40-100° C.) with the more extreme conditions used to remove the ethylene glycol. (Alternatively, once the THF has evaporated the solution can be diluted with water and the product extracted into EtOAc). The residue was purified by column chromatography (2kg silica gel, EtOAc-hexanes gradient 1:1 to 4:1). The appropriate fractions were combined, evaporated and dried to afford 84 g of a white crisp foam (50%), contaminated starting material (17.4 g, 12% recovery) and pure reusable starting material (20 g, 13% recovery). TLC and NMR spectroscopy were consistent with 99% pure product.

[0193] 2′-O-([2-phthalimidoxy)ethyl]-5′-t-butyldiphenylsilyl-5-methyluridine

[0194] 5′-O-tert-Butyldiphenylsilyl-2′-O-(2-hydroxyethyl)-5-methyluridine (20 g, 36.98 mmol) was mixed with triphenylphosphine (11.63g, 44.36mmol) and N-hydroxyphthalimide (7.24 g, 44.36 mmol) and dried over P₂O₅ under high vacuum for two days at 40° C. The reaction mixture was flushed with argon and dissolved in dry THF (369.8 mL, Aldrich, sure seal bottle). Diethyl-azodicarboxylate (6.98 mL, 44.36 mmol) was added dropwise to the reaction mixture with the rate of addition maintained such that the resulting deep red coloration is just discharged before adding the next drop. The reaction mixture was stirred for 4 hrs., after which time TLC (EtOAc:hexane, 60:40) indicated that the reaction was complete. The solvent was evaporated in vacuuo and the residue purified by flash column chromatography (eluted with 60:40 EtOAc:hexane), to yield 2′-O-([2-phthalimidoxy)ethyl]-5′-t-butyldiphenylsilyl-5-methyluridine as white foam (21.819 g, 86%) upon rotary evaporation.

[0195] 5′-O-tert-butyldiphenylsilyl-2′-O-[(2-formadoximinooxy)ethyl]-5-methyluridine

[0196] 2′-O-([2-phthalimidoxy)ethyl]-5′-t-butyldiphenylsilyl-5-methyluridine (3.1 g, 4.5 mmol) was dissolved in dry CH₂Cl₂ (4.5 mL) and methylhydrazine (300 mL, 4.64 mmol) was added dropwise at −10° C. to 0° C. After 1 h the mixture was filtered, the filtrate washed with ice cold CH₂Cl₂, and the combined organic phase was washed with water and brine and dried (anhydrous Na₂SO₄). The solution was filtered and evaporated to afford 2′-O-(aminooxyethyl)thymidine, which was then dissolved in MeOH (67.5 mL). Formaldehyde (20% aqueous solution, w/w, 1.1 eq.) was added and the resulting mixture was stirred for 1 h. The solvent was removed under vacuum and the residue was purified by column chromatography to yield 5′-O-tert-butyldiphenylsilyl-2′-O-[(2-formadoximinooxy) ethyl]-5-methyluridine as white foam (1.95 g, 78%) upon rotary evaporation.

[0197] 5′-O-tert-Butyldiphenylsilyl-2′-O-[N,N dimethylaminooxyethyl]-5-methyluridine

[0198] 5′-O-tert-butyldiphenylsilyl-2′-O-[(2-formadoximinooxy)ethyl]-5-methyluridine (1.77 g, 3.12 mmol) was dissolved in a solution of 1M pyridinium p-toluenesulfonate (PPTS) in dry MeOH (30.6 mL) and cooled to 10° C. under inert atmosphere. Sodium cyanoborohydride (0.39 g, 6.13 mmol) was added and the reaction mixture was stirred. After 10 minutes the reaction was warmed to room temperature and stirred for 2 h. while the progress of the reaction was monitored by TLC (5% MeOH in CH₂Cl₂). Aqueous NaHCO₃ solution (5%, 10 mL) was added and the product was extracted with EtOAc (2×20 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness. This entire procedure was repeated with the resulting residue, with the exception that formaldehyde (20% w/w, 30 mL, 3.37 mol) was added upon dissolution of the residue in the PPTS/MeOH solution. After the extraction and evaporation, the residue was purified by flash column chromatography and (eluted with 5% MeOH in CH₂Cl₂) to afford 5′-O-tert-butyldiphenylsilyl-2′-O-[N,N-dimethylaminooxyethyl]-5-methyluridine as a white foam (14.6 g, 80%) upon rotary evaporation.

[0199] 2′-O-(dimethylaminooxyethyl)-5-methyluridine

[0200] Triethylamine trihydrofluoride (3.91 mL, 24.0 mmol) was dissolved in dry THF and TEA (1.67 mL, 12 mmol, dry, stored over KOH) and added to 5′-O-tert-butyldiphenylsilyl-2′-O-[N,N-dimethylaminooxyethyl]-5-methyluridine (1.40 g, 2.4 mmol). The reaction was stirred at room temperature for 24 hrs and monitored by TLC (5% MeOH in CH₂Cl₂). The solvent was removed under vacuum and the residue purified by flash column chromatography (eluted with 10% MeOH in CH₂Cl₂) to afford 2′-O-(dimethylaminooxyethyl)-5-methyluridine (766 mg, 92.5%) upon rotary evaporation of the solvent.

[0201] 5′-O-DMT-2′ -O-(dimethylaminooxyethyl)-5-methyluridine

[0202] 2′-O-(dimethylaminooxyethyl)-5-methyluridine (750 mg, 2.17 mmol) was dried over P₂O₅ under high vacuum overnight at 40° C., co-evaporated with anhydrous pyridine (20 mL), and dissolved in pyridine (11 mL) under argon atmosphere. 4-dimethylaminopyridine (26.5 mg, 2.60 mmol) and 4,4′-dimethoxytrityl chloride (880 mg, 2.60 mmol) were added to the pyridine solution and the reaction mixture was stirred at room temperature until all of the starting material had reacted. Pyridine was removed under vacuum and the residue was purified by column chromatography (eluted with 10% MeOH in CH₂Cl₂ containing a few drops of pyridine) to yield 5′-O-DMT-2′-O-(dimethylamino-oxyethyl)-5-methyluridine (1-13 g, 80%) upon rotary evaporation.

[0203] 5′-O-DMT-2′-O-(2—N,N-dimethylaminooxyethyl)-5-methyluridine-3′-[(2-cyanoethyl)-N,N-diisopropylphosphoramidite]

[0204] 5′-O-DMT-2′-O-(dimethylaminooxyethyl)-5-methyluridine (1.08 g, 1.67 mmol) was co-evaporated with toluene (20 mL), N,N-diisopropylamine tetrazonide (0.29 g, 1.67 mmol) was added and the mixture was dried over P₂O₅ under high vacuum overnight at 40° C. This was dissolved in anhydrous acetonitrile (8.4 mL) and 2-cyanoethyl-N,N,N¹,N¹-tetraisopropylphosphoramidite (2.12 mL, 6.08 mmol) was added. The reaction mixture was stirred at ambient temperature for 4 h under inert atmosphere. The progress of the reaction was monitored by TLC (hexane:EtOAc 1:1). The solvent was evaporated, then the residue was dissolved in EtOAc (70 mL) and washed with 5% aqueous NaHCO₃ (40 mL). The EtOAc layer was dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue obtained was purified by column chromatography (EtOAc as eluent) to afford 5′-O-DMT-2′-O-(2—N,N-dimethylaminooxyethyl)-5-methyluridine-3′-[(2-cyanoethyl)-N,N-diisopropylphosphoramidite] as a foam (1.04 g, 74.9%) upon rotary evaporation.

[0205] 2′-(Aminooxyethoxy)nucleoside amidites

[0206] 2′-(Aminooxyethoxy)nucleoside amidites (also known in the art as 2′-O-(aminooxyethyl)nucleoside amidites) are prepared as described in the following paragraphs. Adenosine, cytidine and thymidine nucleoside amidites are prepared similarly.

[0207] N2-isobutyryl-6-O-diphenylcarbamoyl-2′-O-(2-ethylacetyl)-5′-O-(4,4′-dimethoxytrityl)guanosine-3′-[(2-cyanoethyl)-N,N-diisopropylphosphoramidite]

[0208] The 2′-O-aminooxyethyl guanosine analog may be obtained by selective 2′-O-alkylation of diaminopurine riboside. Multigram quantities of diaminopurine riboside may be purchased from Schering AG (Berlin) to provide 2′-O-(2-ethylacetyl)diaminopurine riboside along with a minor amount of the 3′-O-isomer. 2′-O-(2-ethylacetyl)diaminopurine riboside may be resolved and converted to 2′-O-(2-ethylacetyl)guanosine by treatment with adenosine deaminase. (McGee, D. P. C., Cook, P. D., Guinosso, C. J., WO 94/02501 A1 940203.) Standard protection procedures should afford 2′-O-(2-ethylacetyl)-5′-O-(4,4′-dimethoxytrityl)guanosine and 2-N-isobutyryl-6-O-diphenylcarbamoyl-2′-O-(2-ethylacetyl)-5′-O-(4,4′-dimethoxytrityl)guanosine which may be reduced to provide 2-N-isobutyryl-6-O-diphenylcarbamoyl-2′-O-(2-hydroxyethyl)-5′-O-(4,4′-dimethoxytrityl)guanosine. As before the hydroxyl group may be displaced by N-hydroxyphthalimide via a Mitsunobu reaction, and the protected nucleoside may be phosphitylated as usual to yield 2—N-isobutyryl-6-O-diphenylcarbamoyl-2′-O-([2-phthalmidoxy]ethyl)-5′-O-(4,4′-dimethoxytrityl)guanosine-3′-[(2-cyanoethyl)-N,N-diisopropylphosphoramidite].

[0209] 2′-dimethylaminoethoxyethoxy (2′-DMAEOE)nucleoside amidites

[0210] 2′-dimethylaminoethoxyethoxy nucleoside amidites (also known in the art as 2′-O-dimethylaminoethoxyethyl, i.e., 2′-O—CH₂—O—CH₂—N(CH₂)₂, or 2′-DMAEOE nucleoside amidites) are prepared as follows. Other nucleoside amidites are prepared similarly.

[0211] 2′-O-[2(2-N,N-dimethylaminoethoxy)ethyl]-5-methyl uridine

[0212] 2[2-(Dimethylamino)ethoxy]ethanol (Aldrich, 6.66 g, 50 mmol) was slowly added to a solution of borane in tetra-hydrofuran (1 M, 10 mL, 10 mmol) with stirring in a 100 mL bomb. (Caution: Hydrogen gas evolves as the solid dissolves). O²-,2′-anhydro-5-methyluridine (1.2 g, 5 mmol), and sodium bicarbonate (2.5 mg) were added and the bomb was sealed, placed in an oil bath and heated to 155° C. for 26 h. then cooled to room temperature. The crude solution was concentrated, the residue was diluted with water (200 mL) and extracted with hexanes (200 mL). The product was extracted from the aqueous layer with EtOAc (3×200 mL) and the combined organic layers were washed once with water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with 5:100:2 MeOH/CH₂Cl₂/TEA) as the eluent. The appropriate fractions were combined and evaporated to afford the product as a white solid.

[0213] 5′-O-dimethoxytrityl-2′-O-[2(2-N,N-dimethylaminoethoxy) ethyl)]-5-methyl uridine

[0214] To 0.5 g (1.3 mmol) of 2′-O-[2(2-N,N-dimethylamino-ethoxy)ethyl)]-5-methyl uridine in anhydrous pyridine (8 mL), was added TEA (0.36 mL) and dimethoxytrityl chloride (DMT-Cl, 0.87 g, 2 eq.) and the reaction was stirred for 1 h. The reaction mixture was poured into water (200 mL) and extracted with CH₂Cl₂ (2×200 mL). The combined CH₂Cl₂ layers were washed with saturated NaHCO₃ solution, followed by saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography (eluted with 5:100:1 MeOH/CH₂Cl₂/TEA) to afford the product.

[0215] 5′-O-Dimethoxytrityl-2′-O-[2(2-N,N-dimethylaminoethoxy)-ethyl)]-5-methyl uridine-3′-O-(cyanoethyl-N,N-diisopropyl)phosphoramidite

[0216] Diisopropylaminotetrazolide (0.6 g) and 2-cyanoethoxy-N,N-diisopropyl phosphoramidite (1.1 mL, 2 eq.) were added to a solution of 5′-O-dimethoxytrityl-2′-O-[2(2-N,N-dimethylaminoethoxy)ethyl)]-5-methyluridine (2.17 g, 3 mmol) dissolved in CH₂Cl₂ (20 mL) under an atmosphere of argon. The reaction mixture was stirred overnight and the solvent evaporated. The resulting residue was purified by silica gel column chromatography with EtOAc as the eluent to afford the title compound.

Example 2

[0217] Oligonucleotide Synthesis

[0218] Unsubstituted and substituted phosphodiester (P═O) oligonucleotides are synthesized on an automated DNA synthesizer (Applied Biosystems model 394) using standard phosphoramidite chemistry with oxidation by iodine.

[0219] Phosphorothioates (P═S) are synthesized similar to phosphodiester oligonucleotides with the following exceptions: thiation was effected by utilizing a 10% w/v solution of 3H-1,2-benzodithiole-3-one 1,1-dioxide in acetonitrile for the oxidation of the phosphite linkages. The thiation reaction step time was increased to 180 sec and preceded by the normal capping step. After cleavage from the CPG column and deblocking in concentrated ammonium hydroxide at 55° C. (12-16 hr), the oligonucleotides were recovered by precipitating with >3 volumes of ethanol from a 1 M NH₄oAc solution. Phosphinate oligonucleotides are prepared as described in U.S. Pat. No. 5,508,270, herein incorporated by reference.

[0220] Alkyl phosphonate oligonucleotides are prepared as described in U.S. Pat. No. 4,469,863, herein incorporated by reference. 3′-Deoxy-3′-methylene phosphonate oligonucleotides are prepared as described in U.S. Pat. Nos. 5,610,289 or 5,625,050, herein incorporated by reference.

[0221] Phosphoramidite oligonucleotides are prepared as described in U.S. Pat. No. 5,256,775 or U.S. Pat. No. 5,366,878, herein incorporated by reference.

[0222] Alkylphosphonothioate oligonucleotides are prepared as described in published PCT applications PCT/US94/00902 and PCT/US93/06976 (published as WO 94/17093 and WO 94/02499, respectively), herein incorporated by reference. 3′-Deoxy-3′-amino phosphoramidate oligonucleotides are prepared as described in U.S. Pat. No. 5,476,925, herein incorporated by reference.

[0223] Phosphotriester oligonucleotides are prepared as described in U.S. Pat. No. 5,023,243, herein incorporated by reference.

[0224] Borano phosphate oligonucleotides are prepared as described in U.S. Pat. Nos. 5,130,302 and 5,177,198, both herein incorporated by reference.

Example 3

[0225] Oligonucleoside Synthesis

[0226] Methylenemethylimino linked oligonucleosides, also identified as MMI linked oligonucleosides, methylenedimethyl-hydrazo linked oligonucleosides, also identified as MDH linked oligonucleosides, and methylenecarbonylamino linked oligonucleosides, also identified as amide-3 linked oligonucleosides, and methyleneaminocarbonyl linked oligo-nucleosides, as well as mixed backbone compounds having, for instance, alternating MMI and P═O or P═S linkages are prepared as described in U.S. Pat. Nos. 5,378,825, 5,386,023, 5,489,677, 5,602,240 and 5,610,289, all of which are herein incorporated by reference.

[0227] Formacetal and thioformacetal linked oligonucleosides are prepared as described in U.S. Pat. Nos. 5,264,562 and 5,264,564, herein incorporated by reference.

[0228] Ethylene oxide linked oligonucleosides are prepared as described in U.S. Pat. No. 5,223,618, herein incorporated by reference.

Example 4 PNA Synthesis

[0229] Peptide nucleic acids (PNAs) are prepared in accordance with any of the various procedures referred to in Peptide Nucleic Acids (PNA): Synthesis, Properties and Potential Applications, Bioorganic & Medicinal Chemistry, 1996, 4, 5-23. They may also be prepared in accordance with U.S. Pat. Nos. 5,539,082, 5,700,922, and 5,719,262, herein incorporated by reference.

Example 5

[0230] Synthesis of Chimeric Oligonucleotides

[0231] Chimeric oligonucleotides, oligonucleosides or mixed oligonucleotides/oligonucleosides of the invention can be of several different types. These include a first type wherein the “gap” segment of linked nucleosides is positioned between 5′ and 3′ “wing” segments of linked nucleosides and a second “open end” type wherein the “gap” segment is located at either the 3′ or the 5′ terminus of the oligomeric compound. Oligonucleotides of the first type are also known in the art as “gapmers” or gapped oligonucleotides. Oligonucleotides of the second type are also known in the art as “hemimers” or “wingmers”.

[0232] [2′-O-Me]—[2′-deoxy]—[2′-O-Me]Chimeric Phosphorothioate Oligonucleotides

[0233] Chimeric oligonucleotides having 2′-O-alkyl phosphorothioate and 2′-deoxy phosphorothioate oligo-nucleotide segments are synthesized using an Applied Biosystems automated DNA synthesizer Model 394, as above. Oligonucleotides are synthesized using the automated synthesizer and 2′-deoxy-5′-dimethoxytrityl-3′-O-phosphor-amidite for the DNA portion and 5′-dimethoxytrityl-2′-O-methyl-3′-O-phosphoramidite for 5′ and 3′ wings. The standard synthesis cycle is modified by incorporating coupling steps with increased reaction times for the 5′-dimethoxytrityl-2′-O-methyl-3′-O-phosphoramidite. The fully protected oligonucleotide is cleaved from the support and deprotected in concentrated ammonia (NH₄OH) for 12-16 hr at 55° C. The deprotected oligo is then recovered by an appropriate method (precipitation, column chromatography, volume reduced in vacuo and analyzed spetrophotometrically for yield and for purity by capillary electrophoresis and by mass spectrometry.

[0234] [2′-O-(2-Methoxyethyl)]—[2′-deoxy]—[2′-O-(Methoxyethyl)]Chimeric Phosphorothioate Oligonucleotides

[0235] [2′-O-(2-methoxyethyl)]—[2′-deoxy]—[−2′-O-(methoxyethyl)]chimeric phosphorothioate oligonucleotides were prepared as per the procedure above for the 2′-O-methyl chimeric oligonucleotide, with the substitution of 2′-O-(methoxyethyl)amidites for the 2′-O-methyl amidites.

[0236] [2′-O-(2-Methoxyethyl)Phosphodiester]—[2′-deoxy Phosphorothioate]—[2′-O-(2-Methoxyethyl)Phosphodiester]Chimeric Oligonucleotides

[0237] [2′-O-(2-methoxyethyl phosphodiester]—[2′-deoxy phosphorothioate]—[2′-O-(methoxyethyl)phosphodiester]chimeric oligonucleotides are prepared as per the above procedure for the 2′-O-methyl chimeric oligonucleotide with the substitution of 2′-O-(methoxyethyl)amidites for the 2′-O-methyl amidites, oxidation with iodine to generate the phosphodiester internucleotide linkages within the wing portions of the chimeric structures and sulfurization utilizing 3,H-1,2 benzodithiole-3-one 1,1 dioxide (Beaucage Reagent) to generate the phosphorothioate internucleotide linkages for the center gap.

[0238] Other chimeric oligonucleotides, chimeric oligonucleosides and mixed chimeric oligonucleotides/oligonucleosides are synthesized according to U.S. Pat. No. 5,623,065, herein incorporated by reference.

Example 6

[0239] Oligonucleotide Isolation

[0240] After cleavage from the controlled pore glass solid support and deblocking in concentrated ammonium hydroxide at 55° C. for 12-16 hours, the oligonucleotides or oligonucleosides are recovered by precipitation out of 1 M NH₄OAc with >3 volumes of ethanol. Synthesized oligonucleotides were analyzed by electrospray mass spectroscopy (molecular weight determination) and by capillary gel electrophoresis and judged to be at least 70% full length material. The relative amounts of phosphorothioate and phosphodiester linkages obtained in the synthesis was determined by the ratio of correct molecular weight relative to the −16 amu product (±32±48). For some studies oligonucleotides were purified by HPLC, as described by Chiang et al., J. Biol. Chem. 1991, 266, 18162-18171. Results obtained with HPLC-purified material were similar to those obtained with non-HPLC purified material.

Example 7

[0241] Oligonucleotide Synthesis—96 Well Plate Format

[0242] Oligonucleotides were synthesized via solid phase P(III) phosphoramidite chemistry on an automated synthesizer capable of assembling 96 sequences simultaneously in a 96-well format. Phosphodiester internucleotide linkages were afforded by oxidation with aqueous iodine. Phosphorothioate internucleotide linkages were generated by sulfurization utilizing 3,H-1,2 benzodithiole-3-one 1,1 dioxide (Beaucage Reagent) in anhydrous acetonitrile. Standard base-protected beta-cyanoethyl-diiso-propyl phosphoramidites were purchased from commercial vendors (e.g. PE-Applied Biosystems, Foster City, Calif., or Pharmacia, Piscataway, N.J.). Non-standard nucleosides are synthesized as per standard or patented methods. They are utilized as base protected beta-cyanoethyldiisopropyl phosphoramidites.

[0243] Oligonucleotides were cleaved from support and deprotected with concentrated NH₄OH at elevated temperature (55-60° C.) for 12-16 hours and the released product then dried in vacuo. The dried product was then re-suspended in sterile water to afford a master plate from which all analytical and test plate samples are then diluted utilizing robotic pipettors.

Example 8

[0244] Oligonucleotide Analysis—96-Well Plate Format

[0245] The concentration of oligonucleotide in each well was assessed by dilution of samples and UV absorption spectroscopy. The full-length integrity of the individual products was evaluated by capillary electrophoresis (CE) in either the 96-well format (Beckman P/ACE™ MDQ) or, for individually prepared samples, on a commercial CE apparatus (e.g., Beckman P/ACE™ 5000, ABI 270). Base and backbone composition was confirmed by mass analysis of the compounds utilizing electrospray-mass spectroscopy. All assay test plates were diluted from the master plate using single and multi-channel robotic pipettors. Plates were judged to be acceptable if at least 85% of the compounds on the plate were at least 85% full length.

Example 9

[0246] Cell Culture and Oligonucleotide Treatment

[0247] The effect of antisense compounds on target nucleic acid expression can be tested in any of a variety of cell types provided that the target nucleic acid is present at measurable levels. This can be routinely determined using, for example, PCR or Northern blot analysis. The following cell types are provided for illustrative purposes, but other cell types can be routinely used, provided that the target is expressed in the cell type chosen. This can be readily determined by methods routine in the art, for example Northern blot analysis, ribonuclease protection assays, or RT-PCR.

[0248] T-24 Cells:

[0249] The human transitional cell bladder carcinoma cell line T-24 was obtained from the American Type Culture Collection (ATCC) (Manassas, Va.). T-24 cells were routinely cultured in complete McCoy's 5A basal media (Invitrogen Corporation, Carlsbad, Calif.) supplemented with 10% fetal calf serum (Invitrogen Corporation, Carlsbad, Calif.), penicillin 100 units per mL, and streptomycin 100 micrograms per mL (Invitrogen Corporation, Carlsbad, Calif.). Cells were routinely passaged by trypsinization and dilution when they reached 90% confluence. Cells were seeded into 96-well plates (Falcon-Primaria #3872) at a density of 7000 cells/well for use in RT-PCR analysis.

[0250] For Northern blotting or other analysis, cells may be seeded onto 100 mm or other standard tissue culture plates and treated similarly, using appropriate volumes of medium and oligonucleotide.

[0251] A549 Cells:

[0252] The human lung carcinoma cell line A549 was obtained from the American Type Culture Collection (ATCC) (Manassas, Va.). A549 cells were routinely cultured in DMEM basal media (Invitrogen Corporation, Carlsbad, Calif.) supplemented with 10% fetal calf serum (Invitrogen Corporation, Carlsbad, Calif.), penicillin 100 units per mL, and streptomycin 100 micrograms per mL (Invitrogen Corporation, Carlsbad, Calif.). Cells were routinely passaged by trypsinization and dilution when they reached 90% confluence.

[0253] NHDF Cells:

[0254] Human neonatal dermal fibroblast (NHDF) were obtained from the Clonetics Corporation (Walkersville, Md.). NHDFs were routinely maintained in Fibroblast Growth Medium (Clonetics Corporation, Walkersville, Md.) supplemented as recommended by the supplier. Cells were maintained for up to 10 passages as recommended by the supplier.

[0255] HEK Cells:

[0256] Human embryonic keratinocytes (HEK) were obtained from the Clonetics Corporation (Walkersville, Md.). HEKs were routinely maintained in Keratinocyte Growth Medium (Clonetics Corporation, Walkersville, Md.) formulated as recommended by the supplier. Cells were routinely maintained for up to 10 passages as recommended by the supplier.

[0257] Treatment with Antisense Compounds:

[0258] When cells reached 70% confluency, they were treated with oligonucleotide. For cells grown in 96-well plates, wells were washed once with 100 μL OPTI-MEM™-1 reduced-serum medium (Invitrogen Corporation, Carlsbad, Calif.) and then treated with 130 μL of OPTI-MEM™-1 containing 3.75 μg/mL LIPOFECTIN™ (Invitrogen Corporation, Carlsbad, Calif.) and the desired concentration of oligonucleotide. After 4-7 hours of treatment, the medium was replaced with fresh medium. Cells were harvested 16-24 hours after oligonucleotide treatment.

[0259] The concentration of oligonucleotide used varies from cell line to cell line. To determine the optimal oligonucleotide concentration for a particular cell line, the cells are treated with a positive control oligonucleotide at a range of concentrations. For human cells the positive control oligonucleotide is selected from either ISIS 13920 (TCCGTCATCGCTCCTCAGGG, SEQ ID NO: 1) which is targeted to human H-ras, or ISIS 18078, (GTGCGCGCGAGCCCGAAATC, SEQ ID NO: 2) which is targeted to human Jun-N-terminal kinase-2 (JNK2). Both controls are 2′-O-methoxyethyl gapmers (2′-O-methoxyethyls shown in bold) with a phosphorothioate backbone. For mouse or rat-cells the positive control oligonucleotide is ISIS 15770, ATGCATTCTGCCCCCAAGGA, SEQ ID NO: 3, a 2′-O-methoxyethyl gapmer (2′-O-methoxyethyls shown in bold) with a phosphorothioate backbone which is targeted to both mouse and rat c-raf. The concentration of positive control oligonucleotide that results in 80% inhibition of c-Ha-ras (for ISIS 13920) or c-raf (for ISIS 15770) mRNA is then utilized as the screening concentration for new oligonucleotides in subsequent experiments for that cell line. If 80% inhibition is not achieved, the lowest concentration of positive control oligonucleotide that results in 60% inhibition of H-ras or c-raf mRNA is then utilized as the oligonucleotide screening concentration in subsequent experiments for that cell line. If 60% inhibition is not achieved, that particular cell line is deemed as unsuitable for oligonucleotide transfection experiments.

Example 10

[0260] Analysis of Oligonucleotide Inhibition of SMRT Expression

[0261] Antisense modulation of SMRT expression can be assayed in a variety of ways known in the art. For example, SMRT mRNA levels can be quantitated by, e.g., Northern blot analysis, competitive polymerase chain reaction (PCR), or real-time PCR (RT-PCR). Real-time quantitative PCR is presently preferred. RNA analysis can be performed on total cellular RNA or poly(A)+ mRNA. The preferred method of RNA analysis of the present invention is the use of total cellular RNA as described in other examples herein. Methods of RNA isolation are taught in, for example, Ausubel, F. M. et al., Current Protocols in Molecular Biology, Volume 1, pp. 4.1.1-4.2.9 and 4.5.1-4.5.3, John Wiley & Sons, Inc., 1993. Northern blot analysis is routine in the art and is taught in, for example, Ausubel, F. M. et al., Current Protocols in Molecular Biology, Volume 1, pp. 4.2.1-4.2.9, John Wiley & Sons, Inc., 1996. Real-time quantitative (PCR) can be conveniently accomplished using the commercially available ABI PRISM™ 7700 Sequence Detection System, available from PE-Applied Biosystems, Foster City, Calif. and used according to manufacturer's instructions.

[0262] Protein levels of SMRT can be quantitated in a variety of ways well known in the art, such as immunoprecipitation, Western blot analysis (immunoblotting), ELISA or fluorescence-activated cell sorting (FACS). Antibodies directed to SMRT can be identified and obtained from a variety of sources, such as the MSRS catalog of antibodies (Aerie Corporation, Birmingham, Mich.), or can be prepared via conventional antibody generation methods. Methods for preparation of polyclonal antisera are taught in, for example, Ausubel, F. M. et al., (Current Protocols in Molecular Biology, Volume 2, pp. 11.12.1-11.12.9, John Wiley & Sons, Inc., 1997). Preparation of monoclonal antibodies is taught in, for example, Ausubel, F. M. et al., (Current Protocols in Molecular Biology, Volume 2, pp. 11.4.1-11.11.5, John Wiley & Sons, Inc., 1997).

[0263] Immunoprecipitation methods are standard in the art and can be found at, for example, Ausubel, F. M. et al., (Current Protocols in Molecular Biology, Volume 2, pp. 10.16.1-10.16.11, John Wiley & Sons, Inc., 1998). Western blot (immunoblot) analysis is standard in the art and can be found at, for example, Ausubel, F. M. et al., (Current Protocols in Molecular Biology, Volume 2, pp. 10.8.1-10.8.21, John Wiley & Sons, Inc., 1997). Enzyme-linked immunosorbent assays (ELISA) are standard in the art and can be found at, for example, Ausubel, F. M. et al., (Current Protocols in Molecular Biology, Volume 2, pp. 11.2.1-11.2.22, John Wiley & Sons, Inc., 1991).

Example 11

[0264] Poly(A)+ mRNA Isolation

[0265] Poly(A)+ mRNA was isolated according to Miura et al., (Clin. Chem., 1996, 42, 1758-1764). Other methods for poly(A)+ mRNA isolation are taught in, for example, Ausubel, F. M. et al., (Current Protocols in Molecular Biology, Volume 1, pp. 4.5.1-4.5.3, John Wiley & Sons, Inc., 1993). Briefly, for cells grown on 96-well plates, growth medium was removed from the cells and each well was washed with 200 μL cold PBS. 60 μL lysis buffer (10 mM Tris-HCl, pH 7.6, 1 mM EDTA, 0.5 M NaCl, 0.5% NP-40, 20 mM vanadyl-ribonucleoside complex) was added to each well, the plate was gently agitated and then incubated at room temperature for five minutes. 55 μL of lysate was transferred to Oligo d(T) coated 96-well plates (AGCT Inc., Irvine Calif.). Plates were incubated for 60 minutes at room temperature, washed 3 times with 200 μL of wash buffer (10 mM Tris-HCl pH 7.6, 1 mM EDTA, 0.3 M NaCl). After the final wash, the plate was blotted on paper towels to remove excess wash buffer and then air-dried for 5 minutes. 60 μL of elution buffer (5 mM Tris-HCl pH 7.6), preheated to 70° C., was added to each well, the plate was incubated on a 90° C. hot plate for 5 minutes, and the eluate was then transferred to a fresh 96-well plate.

[0266] Cells grown on 100 mm or other standard plates may be treated similarly, using appropriate volumes of all solutions.

Example 12

[0267] Total RNA Isolation

[0268] Total RNA was isolated using an RNEASY 96™ kit and buffers purchased from Qiagen Inc. (Valencia, Calif.) following the manufacturer's recommended procedures. Briefly, for cells grown on 96-well plates, growth medium was removed from the cells and each well was washed with 200 μL cold PBS. 150 μL Buffer RLT was added to each well and the plate vigorously agitated for 20 seconds. 150 μL of 70% ethanol was then added to each well and the contents mixed by pipetting three times up and down. The samples were then transferred to the RNEASY 96™ well plate attached to a QIAVAC™ manifold fitted with a waste collection tray and attached to a vacuum source. Vacuum was applied for 1 minute. 500 μL of Buffer RW1 was added to each well of the RNEASY 96™ plate and incubated for 15 minutes and the vacuum was again applied for 1 minute. An additional 500 μL of Buffer RW1 was added to each well of the RNEASY 96™ plate and the vacuum was applied for 2 minutes. 1 mL of Buffer RPE was then added to each well of the RNEASY 96™ plate and the vacuum applied for a period of 90 seconds. The Buffer RPE wash was then repeated and the vacuum was applied for an additional 3 minutes. The plate was then removed from the QIAVAC™ manifold and blotted dry on paper towels. The plate was then re-attached to the QIAVAC™ manifold fitted with a collection tube rack containing 1.2 mL collection tubes. RNA was then eluted by pipetting 170 μL water into each well, incubating 1 minute, and then applying the vacuum for 3 minutes.

[0269] The repetitive pipetting and elution steps may be automated using a QIAGEN Bio-Robot 9604 (Qiagen, Inc., Valencia Calif.). Essentially, after lysing of the cells on the culture plate, the plate is transferred to the robot deck where the pipetting, DNase treatment and elution steps are carried out.

Example 13

[0270] Real-time Quantitative PCR Analysis of SMRT mRNA Levels

[0271] Quantitation of SMRT mRNA levels was determined by real-time quantitative PCR using the ABI PRISM™ 7700 Sequence Detection System (PE-Applied Biosystems, Foster City, Calif.) according to manufacturer's instructions. This is a closed-tube, non-gel-based, fluorescence detection system which allows high-throughput quantitation of polymerase chain reaction (PCR) products in real-time. As opposed to standard PCR in which amplification products are quantitated after the PCR is completed, products in real-time quantitative PCR are quantitated as they accumulate. This is accomplished by including in the PCR reaction an oligonucleotide probe that anneals specifically between the forward and reverse PCR primers, and contains two fluorescent dyes. A reporter dye (e.g., FAM or JOE, obtained from either PE-Applied Biosystems, Foster City, Calif., Operon Technologies Inc., Alameda, Calif. or Integrated DNA Technologies Inc., Coralville, Iowa) is attached to the 5′ end of the probe and a quencher dye (e.g., TAMRA, obtained from either PE-Applied Biosystems, Foster City, Calif., Operon Technologies Inc., Alameda, Calif. or Integrated DNA Technologies Inc., Coralville, Iowa) is attached to the 3′ end of the probe. When the probe and dyes are intact, reporter dye emission is quenched by the proximity of the 3′ quencher dye. During amplification, annealing of the probe to the target sequence creates a substrate that can be cleaved by the 5′-exonuclease activity of Taq polymerase. During the extension phase of the PCR amplification cycle, cleavage of the probe by Taq polymerase releases the reporter dye from the remainder of the probe (and hence from the quencher moiety) and a sequence-specific fluorescent signal is generated. With each cycle, additional reporter dye molecules are cleaved from their respective probes, and the fluorescence intensity is monitored at regular intervals by laser optics built into the ABI PRISM™ 7700 Sequence Detection System. In each assay, a series of parallel reactions containing serial dilutions of mRNA from untreated control samples generates a standard curve that is used to quantitate the percent inhibition after antisense oligonucleotide treatment of test samples.

[0272] Prior to quantitative PCR analysis, primer-probe sets specific to the target gene being measured are evaluated for their ability to be “multiplexed” with a GAPDH amplification reaction. In multiplexing, both the target gene and the internal standard gene GAPDH are amplified concurrently in a single sample. In this analysis, mRNA isolated from untreated cells is serially diluted. Each dilution is amplified in the presence of primer-probe sets specific for GAPDH only, target gene only (“single-plexing”), or both (multiplexing). Following PCR amplification, standard curves of GAPDH and target mRNA signal as a function of dilution are generated from both the single-plexed and multiplexed samples. If both the slope and correlation coefficient of the GAPDH and target signals generated from the multiplexed samples fall within 10% of their corresponding values generated from the single-plexed samples, the primer-probe set specific for that target is deemed multiplexable. Other methods of PCR are also known in the art.

[0273] PCR reagents were obtained from Invitrogen Corporation, (Carlsbad, Calif.). RT-PCR reactions were carried out by adding 20 μL PCR cocktail (2.5×PCR buffer (13 MgCl2), 6.6 mM MgCl2, 375 μM each of DATP, dCTP, dCTP and dGTP, 375 nM each of forward primer and reverse primer, 125 nM of probe, 4 Units RNAse inhibitor, 1.25 Units PLATINUM® Taq, 5 Units MuLV reverse transcriptase, and 2.5×ROX dye) to 96-well plates containing 30 μL total RNA solution. The RT reaction was carried out by incubation for 30 minutes at 48° C. Following a 10 minute incubation at 95° C. to activate the PLATINUM® Taq, 40 cycles of a two-step PCR protocol were carried out: 95° C. for 15 seconds (denaturation) followed by 60° C. for 1.5 minutes (annealing/extension).

[0274] Gene target quantities obtained by real time RT-PCR are normalized using either the expression level of GAPDH, a gene whose expression is constant, or by quantifying total RNA using RiboGreen™ (Molecular Probes, Inc. Eugene, Oreg.). GAPDH expression is quantified by real time RT-PCR, by being run simultaneously with the target, multiplexing, or separately. Total RNA is quantified using RiboGreen™ RNA quantification reagent from Molecular Probes. Methods of RNA quantification by RiboGreen™ are taught in Jones, L. J., et al, (Analytical Biochemistry, 1998, 265, 368-374).

[0275] In this assay, 170 μL of RiboGreen™ working reagent (RiboGreen™ reagent diluted 1:350 in 10 mM Tris-HCl, 1 mM EDTA, pH 7.5) is pipetted into a 96-well plate containing 30 μL purified, cellular RNA. The plate is read in a CytoFluor 4000 (PE Applied Biosystems) with excitation at 480 nm and emission at 520 nm.

[0276] Probes and primers to human SMRT were designed to hybridize to a human SMRT sequence, using published sequence information (GenBank accession number AF125672.1, incorporated herein as SEQ ID NO: 4). For human SMRT the PCR primers were: forward primer: CACACATCGTTGCCGCAG (SEQ ID NO: 5) reverse primer: AAGGTATCAAAAATATACCCTGTAAACCA (SEQ ID NO: 6) and the PCR probe was: FAM-TGGGAAGGAAAGGCAGATGTAAATGATGTG-TAMRA (SEQ ID NO: 7) where FAM is the fluorescent dye and TAMRA is the quencher dye. For human GAPDH the PCR primers were: forward primer: GAAGGTGAAGGTCGGAGTC(SEQ ID NO: 8) reverse primer: GAAGATGGTGATGGGATTTC (SEQ ID NO: 9) and the PCR probe was: 5′ JOE-CAAGCTTCCCGTTCTCAGCC-TAMRA 3′ (SEQ ID NO: 10) where JOE is the fluorescent reporter dye and TAMRA is the quencher dye.

Example 14

[0277] Northern Blot Analysis of SMRT mRNA Levels

[0278] Eighteen hours after antisense treatment, cell monolayers were washed twice with cold PBS and lysed in 1 mL RNAZOL™ (TEL-TEST “B” Inc., Friendswood, Tex.). Total RNA was prepared following manufacturer's recommended protocols. Twenty micrograms of total RNA was fractionated by electrophoresis through 1.2%,agarose gels containing 1.1% formaldehyde using a MOPS buffer system (AMRESCO, Inc. Solon, Ohio). RNA was transferred from the gel to HYBOND™-N+ nylon membranes (Amersham Pharmacia Biotech, Piscataway, N.J.) by overnight capillary transfer using a Northern/Southern Transfer buffer system (TEL-TEST “B” Inc., Friendswood, Tex.). RNA transfer was confirmed by UV visualization. Membranes were fixed by UV cross-linking using a STRATALINKER™ UV Crosslinker 2400 (Stratagene, Inc, La Jolla, Calif.) and then probed using QUICKHYB™ hybridization solution (Stratagene, La Jolla, Calif.) using manufacturer's recommendations for stringent conditions.

[0279] To detect human SMRT, a human SMRT specific probe was prepared by PCR using the forward primer CACACATCGTTGCCGCAG (SEQ ID NO: 5) and the reverse primer AAGGTATCAAAAATATACCCTGTAAACCA (SEQ ID NO: 6). To normalize for variations in loading and transfer efficiency membranes were stripped and probed for human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) RNA (Clontech, Palo Alto, Calif.).

[0280] Hybridized membranes were visualized and quantitated using a PHOSPHORIMAGER™ and IMAGEQUANT™ Software V3.3 (Molecular Dynamics, Sunnyvale, Calif.). Data was normalized to GAPDH levels in untreated controls.

Example 15

[0281] Antisense Inhibition of Human SMRT Expression by Chimeric Phosphorothioate Oligonucleotides having 2′-MOE Wings and a deoxy Gap

[0282] In accordance with the present invention, a series of oligonucleotides were designed to target different regions of the human SMRT RNA, using published sequences (GenBank accession number AF125672.1, incorporated herein as SEQ ID NO: 4; GenBank accession number NM_(—)006312.1, incorporated herein as SEQ ID NO: 11; the complement of residues 39001-260000 of GenBank accession number NT_(—)009459.3, representing a partial genomic sequence of SMRT, incorporated herein as SEQ ID NO: 12; and GenBank accession number S83390.1, incorporated herein as SEQ ID NO: 13). The oligonucleotides are shown in Table 1. “Target site” indicates the first (5′-most) nucleotide number on the particular target sequence to which the oligonucleotide binds. All compounds in Table 1 are chimeric oligonucleotides (“gapmers”) 20 nucleotides in length, composed of a central “gap” region consisting of ten 2′-deoxynucleotides, which is flanked on both sides (5′ and 3′ directions) by five-nucleotide “wings”. The wings are composed of 2′-methoxyethyl (2′-MOE) nucleotides. The internucleoside (backbone) linkages are phosphorothioate (P═S) throughout the oligonucleotide. All cytidine residues are 5-methylcytidines. The compounds were analyzed for their effect on human SMRT mRNA levels by quantitative real-time PCR as described in other examples herein. Data are averages from two experiments in which A549 cells were treated with the anitsense oligonucleotides of the present invention. The positive control for each datapoint is identified in the table by sequence ID number. If present, “N.D.” indicates “no data”. TABLE 1 Inhibition of human SMRT mRNA levels by chimeric phosphorothioate oligonucleotides having 2′-MOE wings and a deoxy gap TARGET CONTROL SEQ ID TARGET % SEQ ID SEQ ID ISIS # REGION NO SITE SEQUENCE INHIB NO NO 121624 5′UTR 4 61 agtcctcgtcatcagctcac 13 14 2 152703 Coding 11 2705 ctcttggcagtggtggccct 63 15 2 152708 Coding 11 6987 atgttcctgcaccgcctggc 82 16 2 195343 5′UTR 4 10 ctccagcgaggctgtgtcct 77 17 2 195344 5′UTR 4 30 tcactggcaccagaaactgc 32 18 2 195345 Start 4 150 tggagcccgacatggtggtg 27 19 2 Codon 195346 Coding 4 635 ccgtggcggcaccagctcca 63 20 2 195347 Coding 4 1203 gctggcccaccctctgcatg 70 21 2 195348 Coding 4 1856 gctgttggcagttttgcggc 21 22 2 195349 Coding 4 2311 ttgacagtggcttcagcctc 24 23 2 195350 Coding 4 3194 aggcttctctgcctccttgt 49 24 2 195351 Coding 4 3752 tgtgctgggaatgcctttgg 75 25 2 195352 Coding 4 5930 ctccttgggcagcaagacgg 73 26 2 195353 Coding 4 7307 gccgccacctggcgaggtga 52 27 2 195354 Stop 4 7670 tgttctgagtcactcgctgt 57 28 2 Codon 195355 3′UTR 4 8323 catcatttacatctgccttt 39 29 2 195356 Coding 11 1048 ggcccaccctgctctgcatg 69 30 2 195357 Coding 11 2159 gcatgtaaggcttcagcctc 0 31 2 195358 Coding 11 2172 ctcattcccagaggcatgta 76 32 2 195359 Coding 11 2210 ttgacagtggctgggccact 38 33 2 195360 Coding 11 3092 gctgcgaaggcctccttgtc 48 34 2 195361 Exon: 12 926 atgaacctaccagaaactgc 33 35 2 Intron Junction 195362 Intron 12 5600 accagacaaggctctgggct 38 36 2 195363 Intron: 12 41188 tcactggcacctgcgggaaa 30 37 2 Exon Junction 195364 Exon: 12 41410 acccccttaccgtgtgcgtc 31 38 2 Intron Junction 195365 Intron 12 72430 cccagtgtcctgaattccta 51 39 2 195366 Intron: 12 82830 cagccttcttctgcagggtg 34 40 2 Exon Junction 195367 Intron: 12 110566 cgctggcccaccctgctggg 48 41 2 Exon Junction 195368 Intron 12 121997 gaccgagttcagccccaggc 30 42 2 195369 Intron: 12 166452 gcatgtaaggctggaaggaa 68 43 2 Exon Junction 195370 Exon: 12 166503 acattcgtacctgggccact 66 44 2 Intron Junction 195371 Intron: 12 184109 ggcttctctgctgagggcag 69 45 2 Exon Junction 195372 Intron: 12 184133 gctgcgaaggctgggaagaa 68 46 2 Exon Junction 195373 Intron 12 195790 cacttgttacttactgccct 63 47 2 195374 Exon: 12 217191 tcatatttacccatgagtgc 63 48 2 Intron Junction 195375 Exon: 12 217330 ggcctgcagacctggcgagg 62 49 2 Intron Junction 195376 coding 13 2392 gccgccacccatgagtgcct 72 50 2

[0283] As shown in Table 1, SEQ ID NOs 15, 16, 17, 20, 21, 24, 25, 26, 27, 28, 30, 32, 34, 39, 41, 43, 44, 45, 46, 47, 48, 49 and 50 demonstrated at least 40% inhibition of human SMRT expression in this assay and are therefore preferred. The target sites to which these preferred sequences are complementary are herein referred to as “preferred target regions ” and are therefore preferred sites for targeting by compounds of the present invention. These preferred target regions are shown in Table 2. The sequences represent the reverse complement of the preferred antisense compounds shown in Table 1. “Target site” indicates the first (5′-most) nucleotide number of the corresponding target nucleic acid. also shown in Table 2 is the species in which each of the preferred target regions was found. TABLE 2 Sequence and position of preferred target regions identified in SMRT. TARGET SEQ ID TARGET REV COMP SEQ ID SITEID NO SITE SEQUENCE OF SEQ ID ACTIVE IN NO 68267 11 2705 agggccaccactgccaagag 15 H. sapiens 51 68272 11 6987 gccaggcggtgcaggaacat 16 H. sapiens 52 113455 4 10 aggacacagcctcgctggag 17 H. sapiens 53 113458 4 635 tggagctggtgccgccacgg 20 H. sapiens 54 113459 4 1203 catgcagagggtgggccagc 21 H. sapiens 55 113462 4 3194 acaaggaggcagagaagcct 24 H. sapiens 56 113463 4 3752 ccaaaggcattcccagcaca 25 H. sapiens 57 113464 4 5930 ccgtcttgctgcccaaggag 26 H. sapiens 58 113465 4 7307 tcacctcgccaggtggcggc 27 H. sapiens 59 113466 4 7670 acagcgagtgactcagaaca 28 H. sapiens 60 113468 11 1048 catgcagagcagggtgggcc 30 H. sapiens 61 113470 11 2172 tacatgcctctgggaatgag 32 H. sapiens 62 113472 11 3092 gacaaggaggccttcgcagc 34 H. sapiens 63 113477 12 72430 taggaattcaggacactggg 39 H. sapiens 64 113479 12 110566 cccagcagggtgggccagcg 41 H. sapiens 65 113481 12 166452 ttccttccagccttacatgc 43 H. sapiens 66 113482 12 166503 agtggcccaggtacgaatgt 44 H. sapiens 67 113483 12 184109 ctgccctcagcagagaagcc 45 H. sapiens 68 113484 12 184133 ttcttcccagccttcgcagc 46 H. sapiens 69 113485 12 195790 agggcagtaagtaacaagtg 47 H. sapiens 70 113486 12 217191 gcactcatgggtaaatatga 48 H. sapiens 71 113487 12 217330 cctcgccaggtctgcaggcc 49 H. sapiens 72 113488 13 2392 aggcactcatgggtggcggc 50 H. sapiens 73

[0284] As these “preferred target regions” have been found by experimentation to be open to, and accessible for, hybridization with the antisense compounds of the present invention, one of skill in the art will recognize or be able to ascertain, using no more than routine experimentation, further embodiments of the invention that encompass other compounds that specifically hybridize to these sites and consequently inhibit the expression of SMRT.

Example 16

[0285] Western Blot Analysis of SMRT Protein Levels

[0286] Western blot analysis (immunoblot analysis) is carried out using standard methods. Cells are harvested 16-20 h after oligonucleotide treatment, washed once with PBS, suspended in Laemmli buffer (100 ul/well), boiled for 5 minutes and loaded on a 16% SDS-PAGE gel. Gels are run for 1.5 hours at 150 V, and transferred to membrane for western blotting. Appropriate primary antibody directed to SMRT is used, with a radiolabeled or fluorescently labeled secondary antibody directed against the primary antibody species. Bands are visualized using a PHOSPHORIMAGER T (Molecular Dynamics, Sunnyvale Calif.).

1 73 1 20 DNA Artificial Sequence Antisense Oligonucleotide 1 tccgtcatcg ctcctcaggg 20 2 20 DNA Artificial Sequence Antisense Oligonucleotide 2 gtgcgcgcga gcccgaaatc 20 3 20 DNA Artificial Sequence Antisense Oligonucleotide 3 atgcattctg cccccaagga 20 4 8686 DNA H. sapiens CDS (157)...(7680) 4 gagtctttga ggacacagcc tcgctggagg cagtttctgg tgccagtgac ggggtggccc 60 gtgagctgat gacgaggact ggcttttaat ccttggtggt gattaagaga aagcttattg 120 gggcctggga gcagctcccc gccgaccccc accacc atg tcg ggc tcc aca cag 174 Met Ser Gly Ser Thr Gln 1 5 cct gtg gca cag acg tgg agg gcc act gag ccc cgc tac ccg ccc cac 222 Pro Val Ala Gln Thr Trp Arg Ala Thr Glu Pro Arg Tyr Pro Pro His 10 15 20 agc ctt tcc tac cca gtg cag atc gcc cgg acg cac acg gac gtc ggg 270 Ser Leu Ser Tyr Pro Val Gln Ile Ala Arg Thr His Thr Asp Val Gly 25 30 35 ctc ctg gag tac cag cac cac tcc cgc gac tat gcc tcc cac ctg tcg 318 Leu Leu Glu Tyr Gln His His Ser Arg Asp Tyr Ala Ser His Leu Ser 40 45 50 ccc ggc tcc atc atc cag ccc cag cgg cgg agg ccc tcc ctg ctg tct 366 Pro Gly Ser Ile Ile Gln Pro Gln Arg Arg Arg Pro Ser Leu Leu Ser 55 60 65 70 gag ttc cag ccc ggg aat gaa cgg tcc cag gag ctc cac ctg cgg cca 414 Glu Phe Gln Pro Gly Asn Glu Arg Ser Gln Glu Leu His Leu Arg Pro 75 80 85 gag tcc cac tca tac ctg ccc gag ctg ggg aag tca gag atg gag ttc 462 Glu Ser His Ser Tyr Leu Pro Glu Leu Gly Lys Ser Glu Met Glu Phe 90 95 100 att gaa agc aag cgc cct cgg cta gag ctg ctg cct gac ccc ctg ctg 510 Ile Glu Ser Lys Arg Pro Arg Leu Glu Leu Leu Pro Asp Pro Leu Leu 105 110 115 cga ccg tca ccc ctg ctg gcc acg ggc cag cct gcg gga tct gaa gac 558 Arg Pro Ser Pro Leu Leu Ala Thr Gly Gln Pro Ala Gly Ser Glu Asp 120 125 130 ctc acc aag gac cgt agc ctg acg ggc aag ctg gaa ccg gtg tct ccc 606 Leu Thr Lys Asp Arg Ser Leu Thr Gly Lys Leu Glu Pro Val Ser Pro 135 140 145 150 ccc agc ccc ccg cac act gac cct gag ctg gag ctg gtg ccg cca cgg 654 Pro Ser Pro Pro His Thr Asp Pro Glu Leu Glu Leu Val Pro Pro Arg 155 160 165 ctg tcc aag gag gag ctg atc cag aac atg gac cgc gtg gac cga gag 702 Leu Ser Lys Glu Glu Leu Ile Gln Asn Met Asp Arg Val Asp Arg Glu 170 175 180 atc acc atg gta gag cag cag atc tct aag ctg aag aag aag cag caa 750 Ile Thr Met Val Glu Gln Gln Ile Ser Lys Leu Lys Lys Lys Gln Gln 185 190 195 cag ctg gag gag gag gct gcc aag ccg ccc gag cct gag aag ccc gtg 798 Gln Leu Glu Glu Glu Ala Ala Lys Pro Pro Glu Pro Glu Lys Pro Val 200 205 210 tca ccg ccg ccc atc gag tcg aag cac cgc agc ctg gtg cag atc atc 846 Ser Pro Pro Pro Ile Glu Ser Lys His Arg Ser Leu Val Gln Ile Ile 215 220 225 230 tac gac gag aac cgg aag aag gct gaa gct gca cat cgg att ctg gaa 894 Tyr Asp Glu Asn Arg Lys Lys Ala Glu Ala Ala His Arg Ile Leu Glu 235 240 245 ggc ctg ggg ccc cag gtg gag ctg ccg ctg tac aac cag ccc tcc gac 942 Gly Leu Gly Pro Gln Val Glu Leu Pro Leu Tyr Asn Gln Pro Ser Asp 250 255 260 acc cgg cag tat cat gag aac atc aaa ata aac cag gcg atg cgg aag 990 Thr Arg Gln Tyr His Glu Asn Ile Lys Ile Asn Gln Ala Met Arg Lys 265 270 275 aag cta atc ttg tac ttc aag agg agg aat cac gct cgg aaa caa tgg 1038 Lys Leu Ile Leu Tyr Phe Lys Arg Arg Asn His Ala Arg Lys Gln Trp 280 285 290 gag cag aag ttc tgc cag cgc tat gac cag ctc atg gag gcc tgg gag 1086 Glu Gln Lys Phe Cys Gln Arg Tyr Asp Gln Leu Met Glu Ala Trp Glu 295 300 305 310 aag aag gtg gag cgc atc gag aac aac ccc cgg cgg cgg gcc aag gag 1134 Lys Lys Val Glu Arg Ile Glu Asn Asn Pro Arg Arg Arg Ala Lys Glu 315 320 325 agc aag gtt cgc gag tac tac gag aag cag ttc cct gag atc cgc aag 1182 Ser Lys Val Arg Glu Tyr Tyr Glu Lys Gln Phe Pro Glu Ile Arg Lys 330 335 340 cag cgc gag ctg cag gag cgc atg cag agg gtg ggc cag cgg ggc agt 1230 Gln Arg Glu Leu Gln Glu Arg Met Gln Arg Val Gly Gln Arg Gly Ser 345 350 355 ggg ctg tcc atg tcg ccc gcc cgc agc gag cac gag gtg tca gag atc 1278 Gly Leu Ser Met Ser Pro Ala Arg Ser Glu His Glu Val Ser Glu Ile 360 365 370 atc gat ggc ctc tca gag cag gag aac ctg gag aag cag atg cgc cag 1326 Ile Asp Gly Leu Ser Glu Gln Glu Asn Leu Glu Lys Gln Met Arg Gln 375 380 385 390 ctg gcc gtg atc ccg ccc atg ctg tac gac gct gac cag cag cgc atc 1374 Leu Ala Val Ile Pro Pro Met Leu Tyr Asp Ala Asp Gln Gln Arg Ile 395 400 405 aag ttc atc aac atg aac ggg ctt atg gcc gac ccc atg aag gtg tac 1422 Lys Phe Ile Asn Met Asn Gly Leu Met Ala Asp Pro Met Lys Val Tyr 410 415 420 aaa gac cgc cag gtc atg aac atg tgg agt gag cag gag aag gag acc 1470 Lys Asp Arg Gln Val Met Asn Met Trp Ser Glu Gln Glu Lys Glu Thr 425 430 435 ttc cgg gag aag ttc atg cag cat ccc aag aac ttt ggc ctg atc gca 1518 Phe Arg Glu Lys Phe Met Gln His Pro Lys Asn Phe Gly Leu Ile Ala 440 445 450 tca ttc ctg gag agg aag aca gtg gct gag tgc gtc ctc tat tac tac 1566 Ser Phe Leu Glu Arg Lys Thr Val Ala Glu Cys Val Leu Tyr Tyr Tyr 455 460 465 470 ctg act aag aag aat gag aac tat aag agc ctg gtg aga cgg agc tat 1614 Leu Thr Lys Lys Asn Glu Asn Tyr Lys Ser Leu Val Arg Arg Ser Tyr 475 480 485 cgg cgc cgc ggc aag agc cag cag caa caa cag cag cag cag cag cag 1662 Arg Arg Arg Gly Lys Ser Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln 490 495 500 cag cag cag cag cag cag cag ccc atg ccc cgc agc agc cag gag gag 1710 Gln Gln Gln Gln Gln Gln Gln Pro Met Pro Arg Ser Ser Gln Glu Glu 505 510 515 aaa gat gag aag gag aag gaa aag gag gcg gag aag gag gag gag aag 1758 Lys Asp Glu Lys Glu Lys Glu Lys Glu Ala Glu Lys Glu Glu Glu Lys 520 525 530 ccg gag gtg gag aac gac aag gaa gac ctc ctc aag gag aag aca gac 1806 Pro Glu Val Glu Asn Asp Lys Glu Asp Leu Leu Lys Glu Lys Thr Asp 535 540 545 550 gac acc tca ggg gag gac aac gac gag aag gag gct gtg gcc tcc aaa 1854 Asp Thr Ser Gly Glu Asp Asn Asp Glu Lys Glu Ala Val Ala Ser Lys 555 560 565 ggc cgc aaa act gcc aac agc cag gga aga cgc aaa ggc cgc atc acc 1902 Gly Arg Lys Thr Ala Asn Ser Gln Gly Arg Arg Lys Gly Arg Ile Thr 570 575 580 cgc tca atg gct aat gag gcc aac agc gag gag gcc atc acc ccc cag 1950 Arg Ser Met Ala Asn Glu Ala Asn Ser Glu Glu Ala Ile Thr Pro Gln 585 590 595 cag agc gcc gag ctg gcc tcc atg gag ctg aat gag agt tct cgc tgg 1998 Gln Ser Ala Glu Leu Ala Ser Met Glu Leu Asn Glu Ser Ser Arg Trp 600 605 610 aca gaa gaa gaa atg gaa aca gcc aag aaa ggt ctc ctg gaa cac ggc 2046 Thr Glu Glu Glu Met Glu Thr Ala Lys Lys Gly Leu Leu Glu His Gly 615 620 625 630 cgc aac tgg tcg gcc atc gcc cgg atg gtg ggc tcc aag act gtg tcg 2094 Arg Asn Trp Ser Ala Ile Ala Arg Met Val Gly Ser Lys Thr Val Ser 635 640 645 cag tgt aag aac ttc tac ttc aac tac aag aag agg cag aac ctc gat 2142 Gln Cys Lys Asn Phe Tyr Phe Asn Tyr Lys Lys Arg Gln Asn Leu Asp 650 655 660 gag atc ttg cag cag cac aag ctg aag atg gag aag gag agg aac gcg 2190 Glu Ile Leu Gln Gln His Lys Leu Lys Met Glu Lys Glu Arg Asn Ala 665 670 675 cgg agg aag aag aag aaa gcg ccg gcg gcg gcc agc gag gag gct gca 2238 Arg Arg Lys Lys Lys Lys Ala Pro Ala Ala Ala Ser Glu Glu Ala Ala 680 685 690 ttc ccg ccc gtg gtg gag gat gag gag atg gag gcg tcg ggc gtg acg 2286 Phe Pro Pro Val Val Glu Asp Glu Glu Met Glu Ala Ser Gly Val Thr 695 700 705 710 gga aat gag gag gag atg gtg gag gag gct gaa gcc act gtc aac aac 2334 Gly Asn Glu Glu Glu Met Val Glu Glu Ala Glu Ala Thr Val Asn Asn 715 720 725 agc tca gac acc gag agc atc ccc tct cct cac act gag gcc gcc aag 2382 Ser Ser Asp Thr Glu Ser Ile Pro Ser Pro His Thr Glu Ala Ala Lys 730 735 740 gac aca ggg cag aat ggg ccc aag ccc cca gcc acc ctg ggc gcc gac 2430 Asp Thr Gly Gln Asn Gly Pro Lys Pro Pro Ala Thr Leu Gly Ala Asp 745 750 755 ggg cca ccc cca ggg cca ccc acc cca cca ccg gag gac atc ccg gcc 2478 Gly Pro Pro Pro Gly Pro Pro Thr Pro Pro Pro Glu Asp Ile Pro Ala 760 765 770 ccc act gag tcc acc ccg gcc tct gaa gcc acc tta gcc cct acg ccc 2526 Pro Thr Glu Ser Thr Pro Ala Ser Glu Ala Thr Leu Ala Pro Thr Pro 775 780 785 790 cca cca gca ccc cca ttt ccc tct tca cct cct cct gtg gtc ccc aag 2574 Pro Pro Ala Pro Pro Phe Pro Ser Ser Pro Pro Pro Val Val Pro Lys 795 800 805 gag gag aag gag gag gag acc gca gca gcg ccc cca gtg gag gag ggg 2622 Glu Glu Lys Glu Glu Glu Thr Ala Ala Ala Pro Pro Val Glu Glu Gly 810 815 820 gag gag cag aag ccc ccc gcg gct gag gag ctg gca gtg gac aca ggg 2670 Glu Glu Gln Lys Pro Pro Ala Ala Glu Glu Leu Ala Val Asp Thr Gly 825 830 835 aag gcc gag gag ccc gtc aag agc gag tgc acg gag gaa gcc gag gag 2718 Lys Ala Glu Glu Pro Val Lys Ser Glu Cys Thr Glu Glu Ala Glu Glu 840 845 850 ggg ccg gcc aag ggc aag gac gcg gag gcc gct gag gcc acg gcc gag 2766 Gly Pro Ala Lys Gly Lys Asp Ala Glu Ala Ala Glu Ala Thr Ala Glu 855 860 865 870 agg gcg ctc aag gca gag aag aag gag ggc ggg agc ggc agg gcc acc 2814 Arg Ala Leu Lys Ala Glu Lys Lys Glu Gly Gly Ser Gly Arg Ala Thr 875 880 885 aca gcc aag agc tcg ggc gcc ccc cag gac agc gac tcc agt gcc acc 2862 Thr Ala Lys Ser Ser Gly Ala Pro Gln Asp Ser Asp Ser Ser Ala Thr 890 895 900 tgc agt gca gac gag gtg gat gag gcc gag ggc ggc gac aag aac cgg 2910 Cys Ser Ala Asp Glu Val Asp Glu Ala Glu Gly Gly Asp Lys Asn Arg 905 910 915 ctg ctg tcc cca agg ccc agc ctc ctc acc ccg act ggc gac ccc cgg 2958 Leu Leu Ser Pro Arg Pro Ser Leu Leu Thr Pro Thr Gly Asp Pro Arg 920 925 930 gcc aat gcc tca ccc cag aag cca ctg gac ctg aag cag ctg aag cag 3006 Ala Asn Ala Ser Pro Gln Lys Pro Leu Asp Leu Lys Gln Leu Lys Gln 935 940 945 950 cga gcg gct gcc atc ccc ccc atc cag gtc acc aaa gtc cat gag ccc 3054 Arg Ala Ala Ala Ile Pro Pro Ile Gln Val Thr Lys Val His Glu Pro 955 960 965 ccc cgg gag gac gca gct ccc acc aag cca gct ccc cca gcc cca ccg 3102 Pro Arg Glu Asp Ala Ala Pro Thr Lys Pro Ala Pro Pro Ala Pro Pro 970 975 980 cca ccg caa aac ctg cag ccg gag agc gac gcc cct cag cag cct ggc 3150 Pro Pro Gln Asn Leu Gln Pro Glu Ser Asp Ala Pro Gln Gln Pro Gly 985 990 995 agc agc ccc cgg ggc aag agc agg agc ccg gca ccc ccc gcc gac aag 3198 Ser Ser Pro Arg Gly Lys Ser Arg Ser Pro Ala Pro Pro Ala Asp Lys 1000 1005 1010 gag gca gag aag cct gtg ttc ttc cca gcc ttc gca gcc gag gcc cag 3246 Glu Ala Glu Lys Pro Val Phe Phe Pro Ala Phe Ala Ala Glu Ala Gln 1015 1020 1025 1030 aag ctg cct ggg gac ccc cct tgc tgg act tcc ggc ctg ccc ttc ccc 3294 Lys Leu Pro Gly Asp Pro Pro Cys Trp Thr Ser Gly Leu Pro Phe Pro 1035 1040 1045 gtg ccc ccc cgt gag gtg atc aag gcc tcc ccg cat gcc ccg gac ccc 3342 Val Pro Pro Arg Glu Val Ile Lys Ala Ser Pro His Ala Pro Asp Pro 1050 1055 1060 tca gcc ttc tcc tac gct cca cct ggt cac cca ctg ccc ctg ggc ctc 3390 Ser Ala Phe Ser Tyr Ala Pro Pro Gly His Pro Leu Pro Leu Gly Leu 1065 1070 1075 cat gac act gcc cgg ccc gtc ctg ccg cgc cca ccc acc atc tcc aac 3438 His Asp Thr Ala Arg Pro Val Leu Pro Arg Pro Pro Thr Ile Ser Asn 1080 1085 1090 ccg cct ccc ctc atc tcc tct gcc aag cac ccc agc gtc ctc gag agg 3486 Pro Pro Pro Leu Ile Ser Ser Ala Lys His Pro Ser Val Leu Glu Arg 1095 1100 1105 1110 caa ata ggt gcc atc tcc caa gga atg tcg gtc cag ctc cac gtc ccg 3534 Gln Ile Gly Ala Ile Ser Gln Gly Met Ser Val Gln Leu His Val Pro 1115 1120 1125 tac tca gag cat gcc aag gcc ccg gtg ggc cct gtc acc atg ggg ctg 3582 Tyr Ser Glu His Ala Lys Ala Pro Val Gly Pro Val Thr Met Gly Leu 1130 1135 1140 ccc ctg ccc atg gac ccc aaa aag ctg gca ccc ttc agc gga gtg aag 3630 Pro Leu Pro Met Asp Pro Lys Lys Leu Ala Pro Phe Ser Gly Val Lys 1145 1150 1155 cag gag cag ctg tcc cca cgg ggc cag gct ggg cca ccg gag agc ctg 3678 Gln Glu Gln Leu Ser Pro Arg Gly Gln Ala Gly Pro Pro Glu Ser Leu 1160 1165 1170 ggg gtg ccc aca gcc cag gag gcg tcc gtg ctg aga ggg aca gct ctg 3726 Gly Val Pro Thr Ala Gln Glu Ala Ser Val Leu Arg Gly Thr Ala Leu 1175 1180 1185 1190 ggc tca gtt ccg ggc gga agc atc acc aaa ggc att ccc agc aca cgg 3774 Gly Ser Val Pro Gly Gly Ser Ile Thr Lys Gly Ile Pro Ser Thr Arg 1195 1200 1205 gtg ccc tcg gac agc gcc atc aca tac cgc ggc tcc atc acc cac ggc 3822 Val Pro Ser Asp Ser Ala Ile Thr Tyr Arg Gly Ser Ile Thr His Gly 1210 1215 1220 acg cca gct gac gtc ctg tac aag ggc acc atc acc agg atc atc ggc 3870 Thr Pro Ala Asp Val Leu Tyr Lys Gly Thr Ile Thr Arg Ile Ile Gly 1225 1230 1235 gag gac agc ccg agt cgc ttg gac cgc ggc cgg gag gac agc ctg ccc 3918 Glu Asp Ser Pro Ser Arg Leu Asp Arg Gly Arg Glu Asp Ser Leu Pro 1240 1245 1250 aag ggc cac gtc atc tac gaa ggc aag aag ggc cac gtc ttg tcc tat 3966 Lys Gly His Val Ile Tyr Glu Gly Lys Lys Gly His Val Leu Ser Tyr 1255 1260 1265 1270 gag ggt ggc atg tct gtg acc cag tgc tcc aag gag gac ggc aga agc 4014 Glu Gly Gly Met Ser Val Thr Gln Cys Ser Lys Glu Asp Gly Arg Ser 1275 1280 1285 agc tca gga ccc ccc cat gag acg gcc gcc ccc aag cgc acc tat gac 4062 Ser Ser Gly Pro Pro His Glu Thr Ala Ala Pro Lys Arg Thr Tyr Asp 1290 1295 1300 atg atg gag ggc cgc gtg ggc aga gcc atc tcc tca gcc agc atc gaa 4110 Met Met Glu Gly Arg Val Gly Arg Ala Ile Ser Ser Ala Ser Ile Glu 1305 1310 1315 ggt ctc atg ggc cgt gcc atc ccg ccg gag cga cac agc ccc cac cac 4158 Gly Leu Met Gly Arg Ala Ile Pro Pro Glu Arg His Ser Pro His His 1320 1325 1330 ctc aaa gag cag cac cac atc cgc ggg tcc atc aca caa ggg atc cct 4206 Leu Lys Glu Gln His His Ile Arg Gly Ser Ile Thr Gln Gly Ile Pro 1335 1340 1345 1350 cgg tcc tac gtg gag gca cag gag gac tac ctg cgt cgg gag gcc aag 4254 Arg Ser Tyr Val Glu Ala Gln Glu Asp Tyr Leu Arg Arg Glu Ala Lys 1355 1360 1365 ctc cta aag cgg gag ggc acg cct ccg ccc cca ccg ccc tca cgg gac 4302 Leu Leu Lys Arg Glu Gly Thr Pro Pro Pro Pro Pro Pro Ser Arg Asp 1370 1375 1380 ctg acc gag gcc tac aag acg cag gcc ctg ggc ccc ctg aag ctg aag 4350 Leu Thr Glu Ala Tyr Lys Thr Gln Ala Leu Gly Pro Leu Lys Leu Lys 1385 1390 1395 ccg gcc cat gag ggc ctg gtg gcc acg gtg aag gag gcg ggc cgc tcc 4398 Pro Ala His Glu Gly Leu Val Ala Thr Val Lys Glu Ala Gly Arg Ser 1400 1405 1410 atc cat gag atc ccg cgc gag gag ctg cgg cac acg ccc gag ctg ccc 4446 Ile His Glu Ile Pro Arg Glu Glu Leu Arg His Thr Pro Glu Leu Pro 1415 1420 1425 1430 ctg gcc ccg cgg ccg ctc aag gag ggc tcc atc acg cag ggc acc ccg 4494 Leu Ala Pro Arg Pro Leu Lys Glu Gly Ser Ile Thr Gln Gly Thr Pro 1435 1440 1445 ctc aag tac gac acc ggc gcg tcc acc act ggc tcc aaa aag cac gac 4542 Leu Lys Tyr Asp Thr Gly Ala Ser Thr Thr Gly Ser Lys Lys His Asp 1450 1455 1460 gta cgc tcc ctc atc ggc agc ccc ggc cgg acg ttc cca ccc gtg cac 4590 Val Arg Ser Leu Ile Gly Ser Pro Gly Arg Thr Phe Pro Pro Val His 1465 1470 1475 ccg ctg gat gtg atg gcc gac gcc cgg gca ctg gaa cgt gcc tgc tac 4638 Pro Leu Asp Val Met Ala Asp Ala Arg Ala Leu Glu Arg Ala Cys Tyr 1480 1485 1490 gag gag agc ctg aag agc cgg cca ggg acc gcc agc agc tcg ggg ggc 4686 Glu Glu Ser Leu Lys Ser Arg Pro Gly Thr Ala Ser Ser Ser Gly Gly 1495 1500 1505 1510 tcc att gcg cgc ggc gcc ccg gtc att gtg cct gag ctg ggt aag ccg 4734 Ser Ile Ala Arg Gly Ala Pro Val Ile Val Pro Glu Leu Gly Lys Pro 1515 1520 1525 cgg cag agc ccc ctg acc tat gag gac cac ggg gca ccc ttt gcc ggc 4782 Arg Gln Ser Pro Leu Thr Tyr Glu Asp His Gly Ala Pro Phe Ala Gly 1530 1535 1540 cac ctc cca cga ggt tcg ccc gtg acc atg cgg gag ccc acg ccg cgc 4830 His Leu Pro Arg Gly Ser Pro Val Thr Met Arg Glu Pro Thr Pro Arg 1545 1550 1555 ctg cag gag ggc agc ctt tcg tcc agc aag gca tcc cag gac cga aag 4878 Leu Gln Glu Gly Ser Leu Ser Ser Ser Lys Ala Ser Gln Asp Arg Lys 1560 1565 1570 ctg acg tcg acg cct cgt gag atc gcc aag tcc ccg cac agc acc gtg 4926 Leu Thr Ser Thr Pro Arg Glu Ile Ala Lys Ser Pro His Ser Thr Val 1575 1580 1585 1590 ccc gag cac cac cca cac ccc atc tcg ccc tat gag cac ctg ctt cgg 4974 Pro Glu His His Pro His Pro Ile Ser Pro Tyr Glu His Leu Leu Arg 1595 1600 1605 ggc gtg agt ggc gtg gac ctg tat cgc agc cac atc ccc ctg gcc ttc 5022 Gly Val Ser Gly Val Asp Leu Tyr Arg Ser His Ile Pro Leu Ala Phe 1610 1615 1620 gac ccc acc tcc ata ccc cgc ggc atc cct ctg gac gca gcc gct gcc 5070 Asp Pro Thr Ser Ile Pro Arg Gly Ile Pro Leu Asp Ala Ala Ala Ala 1625 1630 1635 tac tac ctg ccc cga cac ctg gcc ccc aac ccc acc tac ccg cac ctg 5118 Tyr Tyr Leu Pro Arg His Leu Ala Pro Asn Pro Thr Tyr Pro His Leu 1640 1645 1650 tac cca ccc tac ctc atc cgc ggc tac ccc gac acg gcg gcg ctg gag 5166 Tyr Pro Pro Tyr Leu Ile Arg Gly Tyr Pro Asp Thr Ala Ala Leu Glu 1655 1660 1665 1670 aac cgg cag acc atc atc aat gac tac atc acc tcg cag cag atg cac 5214 Asn Arg Gln Thr Ile Ile Asn Asp Tyr Ile Thr Ser Gln Gln Met His 1675 1680 1685 cac aac acg gcc acc gcc atg gcc cag cga gct gat atg ctg agg ggc 5262 His Asn Thr Ala Thr Ala Met Ala Gln Arg Ala Asp Met Leu Arg Gly 1690 1695 1700 ctc tcg ccc cgc gag tcc tcg ctg gca ctc aac tac gct gcg ggt ccc 5310 Leu Ser Pro Arg Glu Ser Ser Leu Ala Leu Asn Tyr Ala Ala Gly Pro 1705 1710 1715 cga ggc atc atc gac ctg tcc caa gtg cca cac ctg cct gtg ctc gtg 5358 Arg Gly Ile Ile Asp Leu Ser Gln Val Pro His Leu Pro Val Leu Val 1720 1725 1730 ccc ccg aca cca ggc acc cca gcc acc gcc atg gac cgc ctt gcc tac 5406 Pro Pro Thr Pro Gly Thr Pro Ala Thr Ala Met Asp Arg Leu Ala Tyr 1735 1740 1745 1750 ctc ccc acc gcg ccc cag ccc ttc agc agc cgc cac agc agc tcc cca 5454 Leu Pro Thr Ala Pro Gln Pro Phe Ser Ser Arg His Ser Ser Ser Pro 1755 1760 1765 ctc tcc cca gga ggt cca aca cac ttg aca aaa cca acc acc acg tcc 5502 Leu Ser Pro Gly Gly Pro Thr His Leu Thr Lys Pro Thr Thr Thr Ser 1770 1775 1780 tcg tcc gag cgg gag cga gac cgg gat cga gag cgg gac cgg gat cgg 5550 Ser Ser Glu Arg Glu Arg Asp Arg Asp Arg Glu Arg Asp Arg Asp Arg 1785 1790 1795 gag cgg gaa aag tcc atc ctc acg tcc acc acg acg gtg gag cac gca 5598 Glu Arg Glu Lys Ser Ile Leu Thr Ser Thr Thr Thr Val Glu His Ala 1800 1805 1810 ccc atc tgg aga cct ggt aca gag cag agc agc ggc agc agc ggc agc 5646 Pro Ile Trp Arg Pro Gly Thr Glu Gln Ser Ser Gly Ser Ser Gly Ser 1815 1820 1825 1830 agc ggc ggg ggt ggg ggc agc agc agc cgc ccc gcc tcc cac tcc cat 5694 Ser Gly Gly Gly Gly Gly Ser Ser Ser Arg Pro Ala Ser His Ser His 1835 1840 1845 gcc cac cag cac tcg ccc atc tcc cct cgg acc cag gat gcc ctc cag 5742 Ala His Gln His Ser Pro Ile Ser Pro Arg Thr Gln Asp Ala Leu Gln 1850 1855 1860 cag aga ccc agt gtg ctt cac aac aca ggc atg aag ggt atc atc acc 5790 Gln Arg Pro Ser Val Leu His Asn Thr Gly Met Lys Gly Ile Ile Thr 1865 1870 1875 gct gtg gag ccc agc aag ccc acg gtc ctg agg tcc acc tcc acc tcc 5838 Ala Val Glu Pro Ser Lys Pro Thr Val Leu Arg Ser Thr Ser Thr Ser 1880 1885 1890 tca ccc gtt cgc cca gct gcc aca ttc cca cct gcc acc cac tgc cca 5886 Ser Pro Val Arg Pro Ala Ala Thr Phe Pro Pro Ala Thr His Cys Pro 1895 1900 1905 1910 ctg ggc ggc acc ctc gat ggg gtc tac cct acc ctc atg gag ccc gtc 5934 Leu Gly Gly Thr Leu Asp Gly Val Tyr Pro Thr Leu Met Glu Pro Val 1915 1920 1925 ttg ctg ccc aag gag gcc ccc cgg gtc gcc cgg cca gag cgg ccc cga 5982 Leu Leu Pro Lys Glu Ala Pro Arg Val Ala Arg Pro Glu Arg Pro Arg 1930 1935 1940 gca gac acc ggc cat gcc ttc ctc gcc aag ccc cca gcc cgc tcc ggg 6030 Ala Asp Thr Gly His Ala Phe Leu Ala Lys Pro Pro Ala Arg Ser Gly 1945 1950 1955 ctg gag ccc gcc tcc tcc ccc agc aag ggc tcg gag ccc cgg ccc cta 6078 Leu Glu Pro Ala Ser Ser Pro Ser Lys Gly Ser Glu Pro Arg Pro Leu 1960 1965 1970 gtg cct cct gtc tct ggc cac gcc acc atc gcc cgc acc cct gcg aag 6126 Val Pro Pro Val Ser Gly His Ala Thr Ile Ala Arg Thr Pro Ala Lys 1975 1980 1985 1990 aac ctc gca cct cac cac gcc agc ccg gac ccg ccg gcg cca cct gcc 6174 Asn Leu Ala Pro His His Ala Ser Pro Asp Pro Pro Ala Pro Pro Ala 1995 2000 2005 tcg gcc tcg gac ccg cac cgg gaa aag act caa agt aaa ccc ttt tcc 6222 Ser Ala Ser Asp Pro His Arg Glu Lys Thr Gln Ser Lys Pro Phe Ser 2010 2015 2020 atc cag gaa ctg gaa ctc cgt tct ctg ggt tac cac ggc agc agc tac 6270 Ile Gln Glu Leu Glu Leu Arg Ser Leu Gly Tyr His Gly Ser Ser Tyr 2025 2030 2035 agc ccc gaa ggg gtg gag ccc gtc agc cct gtg agc tca ccc agt ctg 6318 Ser Pro Glu Gly Val Glu Pro Val Ser Pro Val Ser Ser Pro Ser Leu 2040 2045 2050 acc cac gac aag ggg ctc ccc aag cac ctg gaa gag ctc gac aag agc 6366 Thr His Asp Lys Gly Leu Pro Lys His Leu Glu Glu Leu Asp Lys Ser 2055 2060 2065 2070 cac ctg gag ggg gag ctg cgg ccc aag cag cca ggc ccc gtg aag ctt 6414 His Leu Glu Gly Glu Leu Arg Pro Lys Gln Pro Gly Pro Val Lys Leu 2075 2080 2085 ggc ggg gag gcc gcc cac ctc cca cac ctg cgg ccg ctg cct gag agc 6462 Gly Gly Glu Ala Ala His Leu Pro His Leu Arg Pro Leu Pro Glu Ser 2090 2095 2100 cag ccc tcg tcc agc ccg ctg ctc cag acc gcc cca ggg gtc aaa ggt 6510 Gln Pro Ser Ser Ser Pro Leu Leu Gln Thr Ala Pro Gly Val Lys Gly 2105 2110 2115 cac cag cgg gtg gtc acc ctg gcc cag cac atc agt gag gtc atc aca 6558 His Gln Arg Val Val Thr Leu Ala Gln His Ile Ser Glu Val Ile Thr 2120 2125 2130 cag gac tac acc cgg cac cac cca cag cag ctc agc gca ccc ctg ccc 6606 Gln Asp Tyr Thr Arg His His Pro Gln Gln Leu Ser Ala Pro Leu Pro 2135 2140 2145 2150 gcc ccc ctc tac tcc ttc cct ggg gcc agc tgc ccc gtc ctg gac ctc 6654 Ala Pro Leu Tyr Ser Phe Pro Gly Ala Ser Cys Pro Val Leu Asp Leu 2155 2160 2165 cgc cgc cca ccc agt gac ctc tac ctc ccg ccc ccg gac cat ggt gcc 6702 Arg Arg Pro Pro Ser Asp Leu Tyr Leu Pro Pro Pro Asp His Gly Ala 2170 2175 2180 ccg gcc cgt ggc tcc ccc cac agc gaa ggg ggc aag agg tct cca gag 6750 Pro Ala Arg Gly Ser Pro His Ser Glu Gly Gly Lys Arg Ser Pro Glu 2185 2190 2195 cca aac aag acg tcg gtc ttg ggt ggt ggt gag gac ggt att gaa cct 6798 Pro Asn Lys Thr Ser Val Leu Gly Gly Gly Glu Asp Gly Ile Glu Pro 2200 2205 2210 gtg tcc cca ccg gag ggc atg acg gag cca ggg cac tcc cgg agt gct 6846 Val Ser Pro Pro Glu Gly Met Thr Glu Pro Gly His Ser Arg Ser Ala 2215 2220 2225 2230 gtg tac ccg ctg ctg tac cgg gat ggg gaa cag acg gag ccc agc agg 6894 Val Tyr Pro Leu Leu Tyr Arg Asp Gly Glu Gln Thr Glu Pro Ser Arg 2235 2240 2245 atg ggc tcc aag tct cca ggc aac acc agc cag ccg cca gcc ttc ttc 6942 Met Gly Ser Lys Ser Pro Gly Asn Thr Ser Gln Pro Pro Ala Phe Phe 2250 2255 2260 agc aag ctg acc gag agc aac tcc gcc atg gtc aag tcc aag aag caa 6990 Ser Lys Leu Thr Glu Ser Asn Ser Ala Met Val Lys Ser Lys Lys Gln 2265 2270 2275 gag atc aac aag aag ctg aac acc cac aac cgg aat gag cct gaa tac 7038 Glu Ile Asn Lys Lys Leu Asn Thr His Asn Arg Asn Glu Pro Glu Tyr 2280 2285 2290 aat atc agc cag cct ggg acg gag atc ttc aat atg ccc gcc atc acc 7086 Asn Ile Ser Gln Pro Gly Thr Glu Ile Phe Asn Met Pro Ala Ile Thr 2295 2300 2305 2310 gga aca ggc ctt atg acc tat aga agc cag gcg gtg cag gaa cat gcc 7134 Gly Thr Gly Leu Met Thr Tyr Arg Ser Gln Ala Val Gln Glu His Ala 2315 2320 2325 agc acc aac atg ggg ctg gag gcc ata att aga aag gca ctc atg ggt 7182 Ser Thr Asn Met Gly Leu Glu Ala Ile Ile Arg Lys Ala Leu Met Gly 2330 2335 2340 aaa tat gac cag tgg gaa gag tcc ccg ccg ctc agc gcc aat gct ttt 7230 Lys Tyr Asp Gln Trp Glu Glu Ser Pro Pro Leu Ser Ala Asn Ala Phe 2345 2350 2355 aac cct ctg aat gcc agt gcc agc ctg ccc gct gct atg ccc ata acc 7278 Asn Pro Leu Asn Ala Ser Ala Ser Leu Pro Ala Ala Met Pro Ile Thr 2360 2365 2370 gct gct gac gga cgg agt gac cac aca ctc acc tcg cca ggt ggc ggc 7326 Ala Ala Asp Gly Arg Ser Asp His Thr Leu Thr Ser Pro Gly Gly Gly 2375 2380 2385 2390 ggg aag gcc aag gtc tct ggc aga ccc agc agc cga aaa gcc aag tcc 7374 Gly Lys Ala Lys Val Ser Gly Arg Pro Ser Ser Arg Lys Ala Lys Ser 2395 2400 2405 ccg gcc ccg ggc ctg gca tct ggg gac cgg cca ccc tct gtc tcc tca 7422 Pro Ala Pro Gly Leu Ala Ser Gly Asp Arg Pro Pro Ser Val Ser Ser 2410 2415 2420 gtg cac tcg gag gga gac tgc aac cgc cgg acg ccg ctc acc aac cgc 7470 Val His Ser Glu Gly Asp Cys Asn Arg Arg Thr Pro Leu Thr Asn Arg 2425 2430 2435 gtg tgg gag gac agg ccc tcg tcc gca ggt tcc acg cca ttc ccc tac 7518 Val Trp Glu Asp Arg Pro Ser Ser Ala Gly Ser Thr Pro Phe Pro Tyr 2440 2445 2450 aac ccc ctg atc atg cgg ctg cag gcg ggt gtc atg gct tcc cca ccc 7566 Asn Pro Leu Ile Met Arg Leu Gln Ala Gly Val Met Ala Ser Pro Pro 2455 2460 2465 2470 cca ccg ggc ctc ccc gcg ggc agc ggg ccc ctc gct ggc ccc cac cac 7614 Pro Pro Gly Leu Pro Ala Gly Ser Gly Pro Leu Ala Gly Pro His His 2475 2480 2485 gcc tgg gac gag gag ccc aag cca ctg ctc tgc tcg cag tac gag aca 7662 Ala Trp Asp Glu Glu Pro Lys Pro Leu Leu Cys Ser Gln Tyr Glu Thr 2490 2495 2500 ctc tcc gac agc gag tga ctcagaacag ggcggggggg ggcgggcggt gtcaggtccc 7720 Leu Ser Asp Ser Glu 2505 agcgagccac aggaacggcc ctgcaggagc ggggcggctg ccgactcccc caaccaagga 7780 aggagcccct gagtccgcct gcgcctccat ccatctgtcc gtccagagcc ggcatccttg 7840 cctgtctaaa gccttaacta agactcccgc cccgggctgg ccctgtgcag accttactca 7900 ggggatgttt acctggtgct cgggaaggga ggggaagggg ccggggaggg ggcacggcag 7960 gcgtgtggca gccacacaca ggcggccagg gcggccaggg acccaaagca ggatgaccac 8020 gcacctccac gccactgcct cccccgaatg catttggaac caaagtctaa actgagctcg 8080 cagcccccgc gccctccctc cgcctcccat cccgcttagc gctctggaca gatggacgca 8140 ggccctgtcc agcccccagt gcgctcgttc cggtccccac agactgcccc agccaacgag 8200 attgctggaa accaagtcag gccaggtggg cggacaaaag ggccaggtgc ggcctggggg 8260 gaacggatgc tccgaggact ggactgtttt tttcacacat cgttgccgca gcggtgggaa 8320 ggaaaggcag atgtaaatga tgtgttggtt tacagggtat atttttgata ccttcaatga 8380 attaattcag atgttttacg caaggaagga cttacccagt attactgctg ctgtgctttt 8440 gatctctgct taccgttcaa gaggcgtgtg caggccgaca gtcggtgacc ccatcactcg 8500 caggaccaag ggggcgggga ctgctcgtca cgccccgctg tgtcctccct ccctcccttc 8560 cttgggcaga atgaattcga tgcgtattct gtggccgcca tttgcgcagg gtggtggtat 8620 tctgtcattt acacacgtcg ttctaattaa aaagcgaatt atactccaaa aaaaaaaaaa 8680 aaaaaa 8686 5 18 DNA Artificial Sequence PCR Primer 5 cacacatcgt tgccgcag 18 6 29 DNA Artificial Sequence PCR Primer 6 aaggtatcaa aaatataccc tgtaaacca 29 7 30 DNA Artificial Sequence PCR Probe 7 tgggaaggaa aggcagatgt aaatgatgtg 30 8 19 DNA Artificial Sequence PCR Primer 8 gaaggtgaag gtcggagtc 19 9 20 DNA Artificial Sequence PCR Primer 9 gaagatggtg atgggatttc 20 10 20 DNA Artificial Sequence PCR Probe 10 caagcttccc gttctcagcc 20 11 8561 DNA Homo sapiens CDS (2)...(7555) 11 c atg tcg ggc tcc aca cag ctt gtg gca cag acg tgg agg gcc act gag 49 Met Ser Gly Ser Thr Gln Leu Val Ala Gln Thr Trp Arg Ala Thr Glu 1 5 10 15 ccc cgc tac ccg ccc cac agc ctt tcc tac cca gtg cag atc gcc cgg 97 Pro Arg Tyr Pro Pro His Ser Leu Ser Tyr Pro Val Gln Ile Ala Arg 20 25 30 acg cac acg gac gtc ggg ctc ctg gag tac cag cac cac tcc cgc gac 145 Thr His Thr Asp Val Gly Leu Leu Glu Tyr Gln His His Ser Arg Asp 35 40 45 tat gcc tcc cac ctg tcg ccg ggc tcc atc atc cag ccc cag cgg cgg 193 Tyr Ala Ser His Leu Ser Pro Gly Ser Ile Ile Gln Pro Gln Arg Arg 50 55 60 agg ccc tcc ctg ctg tct gag ttc cag ccc ggg aat gaa cgg tcc cag 241 Arg Pro Ser Leu Leu Ser Glu Phe Gln Pro Gly Asn Glu Arg Ser Gln 65 70 75 80 gag ctc cac ctg cgg cca gag tcc cac tca tac ctg ccc gag ctg ggg 289 Glu Leu His Leu Arg Pro Glu Ser His Ser Tyr Leu Pro Glu Leu Gly 85 90 95 aag tca gag atg gag ttc att gaa agc aag cgc cct cgg cta gag ctg 337 Lys Ser Glu Met Glu Phe Ile Glu Ser Lys Arg Pro Arg Leu Glu Leu 100 105 110 ctg cct gac ccc ctg ctg cga ccg tca ccc ctg ctg gcc acg ggc cag 385 Leu Pro Asp Pro Leu Leu Arg Pro Ser Pro Leu Leu Ala Thr Gly Gln 115 120 125 cct gcg gga tct gaa gac ctc acc aag gac cgt agc ctg acg ggc aag 433 Pro Ala Gly Ser Glu Asp Leu Thr Lys Asp Arg Ser Leu Thr Gly Lys 130 135 140 ctg gaa ccg gtg tct ccc ccc agc ccc ccg cac act gac cct gag ctg 481 Leu Glu Pro Val Ser Pro Pro Ser Pro Pro His Thr Asp Pro Glu Leu 145 150 155 160 gag ctg gtg ccg cca cgg ctg tcc aag gag gag ctg atc cag aac atg 529 Glu Leu Val Pro Pro Arg Leu Ser Lys Glu Glu Leu Ile Gln Asn Met 165 170 175 gac cgc gtg gac cga gag atc acc atg gta gag cag cag atc tct aag 577 Asp Arg Val Asp Arg Glu Ile Thr Met Val Glu Gln Gln Ile Ser Lys 180 185 190 ctg aag aag aag cag caa cag ctg gag gag gag gct gcc aag ccg ccc 625 Leu Lys Lys Lys Gln Gln Gln Leu Glu Glu Glu Ala Ala Lys Pro Pro 195 200 205 gag cct gag aag ccc gtg tca ccg ccg ccc atc gag tcg aag cac cgc 673 Glu Pro Glu Lys Pro Val Ser Pro Pro Pro Ile Glu Ser Lys His Arg 210 215 220 agc ctg gtg cag atc atc tac gac gag aac cgg aag aag gct gaa gct 721 Ser Leu Val Gln Ile Ile Tyr Asp Glu Asn Arg Lys Lys Ala Glu Ala 225 230 235 240 gca cat cgg att ctg gaa ggc ctg ggg ccc cag gtg gag ctg ccg ctg 769 Ala His Arg Ile Leu Glu Gly Leu Gly Pro Gln Val Glu Leu Pro Leu 245 250 255 tac aac cag ccc tcc gac acc cgg cag tat cat gag aac atc aaa ata 817 Tyr Asn Gln Pro Ser Asp Thr Arg Gln Tyr His Glu Asn Ile Lys Ile 260 265 270 aac cag gcg atg cgg aag aag cta atc ttg tac ttc aag agg agg aat 865 Asn Gln Ala Met Arg Lys Lys Leu Ile Leu Tyr Phe Lys Arg Arg Asn 275 280 285 cac gct cgg aaa caa tgg aag cag aag ttc tgc cag cgc tat gac cag 913 His Ala Arg Lys Gln Trp Lys Gln Lys Phe Cys Gln Arg Tyr Asp Gln 290 295 300 ctc atg gag gcc ttg gaa aaa aag gtg gag cgc atc gaa aac aac ccg 961 Leu Met Glu Ala Leu Glu Lys Lys Val Glu Arg Ile Glu Asn Asn Pro 305 310 315 320 cgc cgg cgg gcc aag gag agc aag gtg cgc gag tac tac gaa aag cag 1009 Arg Arg Arg Ala Lys Glu Ser Lys Val Arg Glu Tyr Tyr Glu Lys Gln 325 330 335 ttc cct gag atc cgc aag cag cgc gag ctg cag gag cgc atg cag agc 1057 Phe Pro Glu Ile Arg Lys Gln Arg Glu Leu Gln Glu Arg Met Gln Ser 340 345 350 agg gtg ggc cag cgg ggc agt ggg ctg tcc atg tcg gcc gcc cgc agc 1105 Arg Val Gly Gln Arg Gly Ser Gly Leu Ser Met Ser Ala Ala Arg Ser 355 360 365 gag cac gag gtg tca gag atc atc gat ggc ctc tca gag cag gag aac 1153 Glu His Glu Val Ser Glu Ile Ile Asp Gly Leu Ser Glu Gln Glu Asn 370 375 380 ctg gag aag cag atg cgc cag ctg gcc gtg atc ccg ccc atg ctg tac 1201 Leu Glu Lys Gln Met Arg Gln Leu Ala Val Ile Pro Pro Met Leu Tyr 385 390 395 400 gac gct gac cag cag cgc atc aag ttc atc aac atg aac ggg ctt atg 1249 Asp Ala Asp Gln Gln Arg Ile Lys Phe Ile Asn Met Asn Gly Leu Met 405 410 415 gcc gac ccc atg aag gtg tac aaa gac cgc cag gtc atg aac atg tgg 1297 Ala Asp Pro Met Lys Val Tyr Lys Asp Arg Gln Val Met Asn Met Trp 420 425 430 agt gag cag gag aag gag acc ttc cgg gag aag ttc atg cag cat ccc 1345 Ser Glu Gln Glu Lys Glu Thr Phe Arg Glu Lys Phe Met Gln His Pro 435 440 445 aag aac ttt ggc ctg atc gca tca ttc ctg gag agg aag aca gtg gct 1393 Lys Asn Phe Gly Leu Ile Ala Ser Phe Leu Glu Arg Lys Thr Val Ala 450 455 460 gag tgc gtc ctc tat tac tac ctg act aag aag aat gag aac tat aag 1441 Glu Cys Val Leu Tyr Tyr Tyr Leu Thr Lys Lys Asn Glu Asn Tyr Lys 465 470 475 480 agc ctg gtg aga cgg agc tat cgg cgc cgc ggc aag agc cag cag caa 1489 Ser Leu Val Arg Arg Ser Tyr Arg Arg Arg Gly Lys Ser Gln Gln Gln 485 490 495 caa cag cag cag cag cag cag cag cag cag cag cag cag cag ccc atg 1537 Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Pro Met 500 505 510 ccc cgc agc agc cag gag gag aaa gat gag aag gag aag gaa aag gag 1585 Pro Arg Ser Ser Gln Glu Glu Lys Asp Glu Lys Glu Lys Glu Lys Glu 515 520 525 gcg gag aag gag gag gag aag ccg gag gtg gag aac gac aag gaa gac 1633 Ala Glu Lys Glu Glu Glu Lys Pro Glu Val Glu Asn Asp Lys Glu Asp 530 535 540 ctc ctc aag gag aag aca gac gac acc tca ggg gag gac aac gac gag 1681 Leu Leu Lys Glu Lys Thr Asp Asp Thr Ser Gly Glu Asp Asn Asp Glu 545 550 555 560 aag gag gct gtg gcc tcc aaa ggc cgc aaa act gcc aac agc cag gga 1729 Lys Glu Ala Val Ala Ser Lys Gly Arg Lys Thr Ala Asn Ser Gln Gly 565 570 575 aga cgc aaa ggc cgc atc acc cgc tca atg gct aat gag gcc aac agc 1777 Arg Arg Lys Gly Arg Ile Thr Arg Ser Met Ala Asn Glu Ala Asn Ser 580 585 590 gag gag gcc atc acc ccc cag cag agc gcc gag ctg gcc tcc atg gag 1825 Glu Glu Ala Ile Thr Pro Gln Gln Ser Ala Glu Leu Ala Ser Met Glu 595 600 605 ctg aat gag agt tct cgc tgg aca gaa gaa gaa atg gaa aca gcc aag 1873 Leu Asn Glu Ser Ser Arg Trp Thr Glu Glu Glu Met Glu Thr Ala Lys 610 615 620 aaa ggt ctc ctg gaa cac ggc cgc aac tgg tcg gcc atc gcc cgg atg 1921 Lys Gly Leu Leu Glu His Gly Arg Asn Trp Ser Ala Ile Ala Arg Met 625 630 635 640 gtg ggc tcc aag act gtg tcg cag tgt aag aac ttc tac ttc aac tac 1969 Val Gly Ser Lys Thr Val Ser Gln Cys Lys Asn Phe Tyr Phe Asn Tyr 645 650 655 aag aag agg cag aac ctc gat gag atc ttg cag cag cac aag ctg aag 2017 Lys Lys Arg Gln Asn Leu Asp Glu Ile Leu Gln Gln His Lys Leu Lys 660 665 670 atg gag aag gag agg aac gcg cgg agg aag aag aag aaa gcg ccg gcg 2065 Met Glu Lys Glu Arg Asn Ala Arg Arg Lys Lys Lys Lys Ala Pro Ala 675 680 685 gcg gcc agc gag gag gct gca ttc ccg ccc gtg gtg gag gat gag gag 2113 Ala Ala Ser Glu Glu Ala Ala Phe Pro Pro Val Val Glu Asp Glu Glu 690 695 700 atg gag gcg tcg ggc gtg agc gga aat gag gag gag atg gtg gag gag 2161 Met Glu Ala Ser Gly Val Ser Gly Asn Glu Glu Glu Met Val Glu Glu 705 710 715 720 gct gaa gcc tta cat gcc tct ggg aat gag gtg ccc aga ggg gaa tgc 2209 Ala Glu Ala Leu His Ala Ser Gly Asn Glu Val Pro Arg Gly Glu Cys 725 730 735 agt ggc cca gcc act gtc aac aac agc tca gac acc gag agc atc ccc 2257 Ser Gly Pro Ala Thr Val Asn Asn Ser Ser Asp Thr Glu Ser Ile Pro 740 745 750 tct cct cac act gag gcc gcc aag gac aca ggg cag aat ggg ccc aag 2305 Ser Pro His Thr Glu Ala Ala Lys Asp Thr Gly Gln Asn Gly Pro Lys 755 760 765 ccc cca gcc acc ctg ggc gcc gac ggg cca ccc cca ggc cca ccc acc 2353 Pro Pro Ala Thr Leu Gly Ala Asp Gly Pro Pro Pro Gly Pro Pro Thr 770 775 780 cca cca cgg agg aca tcc cgg gcc ccc att gag ccc acc ccg gcc tct 2401 Pro Pro Arg Arg Thr Ser Arg Ala Pro Ile Glu Pro Thr Pro Ala Ser 785 790 795 800 gaa gcc acc gga gcc cct acg ccc cca cca gca ccc cca tcg ccc tct 2449 Glu Ala Thr Gly Ala Pro Thr Pro Pro Pro Ala Pro Pro Ser Pro Ser 805 810 815 gca cct cct cct gtg gtc ccc aag gag gag aag gag gag gag acc gca 2497 Ala Pro Pro Pro Val Val Pro Lys Glu Glu Lys Glu Glu Glu Thr Ala 820 825 830 gca gcg ccc cca gtg gag gag ggg gag gag cag aag ccc ccc gcg gct 2545 Ala Ala Pro Pro Val Glu Glu Gly Glu Glu Gln Lys Pro Pro Ala Ala 835 840 845 gag gag ctg gca gtg gac aca ggg aag gcc gag gag ccc gtc aag agc 2593 Glu Glu Leu Ala Val Asp Thr Gly Lys Ala Glu Glu Pro Val Lys Ser 850 855 860 gag tgc acg gag gaa gcc gag gag ggg ccg gcc aag ggc aag gac gcg 2641 Glu Cys Thr Glu Glu Ala Glu Glu Gly Pro Ala Lys Gly Lys Asp Ala 865 870 875 880 gag gcc gct gag gcc acg gcc gag ggg gcg ctc aag gca gag aag aag 2689 Glu Ala Ala Glu Ala Thr Ala Glu Gly Ala Leu Lys Ala Glu Lys Lys 885 890 895 gag ggc ggg agc ggc agg gcc acc act gcc aag agc tcg ggc gcc ccc 2737 Glu Gly Gly Ser Gly Arg Ala Thr Thr Ala Lys Ser Ser Gly Ala Pro 900 905 910 cag gac agc gac tcc agt gct acc tgc agt gca gac gag gtg gat gag 2785 Gln Asp Ser Asp Ser Ser Ala Thr Cys Ser Ala Asp Glu Val Asp Glu 915 920 925 gcc gag ggc ggc gac aag aac cgg ctg ctg tcc cca agg ccc agc ctc 2833 Ala Glu Gly Gly Asp Lys Asn Arg Leu Leu Ser Pro Arg Pro Ser Leu 930 935 940 ctc acc ccg act ggc gac ccc cgg gcc aat gcc tca ccc cag aag cca 2881 Leu Thr Pro Thr Gly Asp Pro Arg Ala Asn Ala Ser Pro Gln Lys Pro 945 950 955 960 ctg gac ctg aag cag ctg aag cag cga gcg gct gcc atc ccc ccc atc 2929 Leu Asp Leu Lys Gln Leu Lys Gln Arg Ala Ala Ala Ile Pro Pro Ile 965 970 975 cag gtc acc aaa gtc cat gag ccc ccc cgg gag gac gca gct ccc acc 2977 Gln Val Thr Lys Val His Glu Pro Pro Arg Glu Asp Ala Ala Pro Thr 980 985 990 aag cca gct ccc cca gcc cca ccg cca ccg caa aac ctg cag ccg gag 3025 Lys Pro Ala Pro Pro Ala Pro Pro Pro Pro Gln Asn Leu Gln Pro Glu 995 1000 1005 agc gac gcc cct cag cag cct ggc agc agc ccc cgg ggc aag agc agg 3073 Ser Asp Ala Pro Gln Gln Pro Gly Ser Ser Pro Arg Gly Lys Ser Arg 1010 1015 1020 agc ccg gca ccc ccc gcc gac aag gag gcc ttc gca gcc gag gcc cag 3121 Ser Pro Ala Pro Pro Ala Asp Lys Glu Ala Phe Ala Ala Glu Ala Gln 1025 1030 1035 1040 aag ctg cct ggg gac ccc cct tgc tgg act tcc ggc ctg ccc ttc ccc 3169 Lys Leu Pro Gly Asp Pro Pro Cys Trp Thr Ser Gly Leu Pro Phe Pro 1045 1050 1055 gtg ccc ccc cgt gag gtg atc aag gcc tcc ccg cat gcc ccg gac ccc 3217 Val Pro Pro Arg Glu Val Ile Lys Ala Ser Pro His Ala Pro Asp Pro 1060 1065 1070 tca gcc ttc tcc tac gct cca cct ggt cac cca ctg ccc ctg ggc ctc 3265 Ser Ala Phe Ser Tyr Ala Pro Pro Gly His Pro Leu Pro Leu Gly Leu 1075 1080 1085 cat gac act gcc cgg ccc gtc ctg ccg cgc cca ccc acc atc tcc aac 3313 His Asp Thr Ala Arg Pro Val Leu Pro Arg Pro Pro Thr Ile Ser Asn 1090 1095 1100 ccg cct ccc ctc atc tcc tct gcc aag cac ccc agc gtc ctc gag agg 3361 Pro Pro Pro Leu Ile Ser Ser Ala Lys His Pro Ser Val Leu Glu Arg 1105 1110 1115 1120 caa ata ggt gcc atc tcc caa gga atg tcg gtc cag ctc cac gtc ccg 3409 Gln Ile Gly Ala Ile Ser Gln Gly Met Ser Val Gln Leu His Val Pro 1125 1130 1135 tac tca gag cat gcc aag gcc ccg gtg ggc cct gtc acc atg ggg ctg 3457 Tyr Ser Glu His Ala Lys Ala Pro Val Gly Pro Val Thr Met Gly Leu 1140 1145 1150 ccc ctg ccc atg gac ccc aaa aag ctg gca ccc ttc agc gga gtg aag 3505 Pro Leu Pro Met Asp Pro Lys Lys Leu Ala Pro Phe Ser Gly Val Lys 1155 1160 1165 cag gag cag ctg tcc cca cgg ggc cag gct ggg cca ccg gag agc ctg 3553 Gln Glu Gln Leu Ser Pro Arg Gly Gln Ala Gly Pro Pro Glu Ser Leu 1170 1175 1180 ggg gtg ccc aca gcc cag gag gcg tcc gtg ctg aga ggg aca gct ctg 3601 Gly Val Pro Thr Ala Gln Glu Ala Ser Val Leu Arg Gly Thr Ala Leu 1185 1190 1195 1200 ggc tca gtt ccg ggc gga agc atc acc aaa ggc att ccc agc aca cgg 3649 Gly Ser Val Pro Gly Gly Ser Ile Thr Lys Gly Ile Pro Ser Thr Arg 1205 1210 1215 gtg ccc tcg gac agc gcc atc aca tac cgc ggc tcc atc acc cac ggc 3697 Val Pro Ser Asp Ser Ala Ile Thr Tyr Arg Gly Ser Ile Thr His Gly 1220 1225 1230 acg cca gct gac gtc ctg tac aag ggc acc atc acc agg atc atc ggc 3745 Thr Pro Ala Asp Val Leu Tyr Lys Gly Thr Ile Thr Arg Ile Ile Gly 1235 1240 1245 gag gac agc ccg agt cgc ttg gac cgc ggc cgg gag gac agc ctg ccc 3793 Glu Asp Ser Pro Ser Arg Leu Asp Arg Gly Arg Glu Asp Ser Leu Pro 1250 1255 1260 aag ggc cac gtc atc tac gaa ggc aag aag ggc cac gtc ttg tcc tat 3841 Lys Gly His Val Ile Tyr Glu Gly Lys Lys Gly His Val Leu Ser Tyr 1265 1270 1275 1280 gag ggt ggc atg tct gtg acc cag tgc tcc aag gag gac ggc aga agc 3889 Glu Gly Gly Met Ser Val Thr Gln Cys Ser Lys Glu Asp Gly Arg Ser 1285 1290 1295 agc tca gga ccc ccc cat gag acg gcc gcc ccc aag cgc acc tat gac 3937 Ser Ser Gly Pro Pro His Glu Thr Ala Ala Pro Lys Arg Thr Tyr Asp 1300 1305 1310 atg atg gag ggc cgc gtg ggc aga gcc atc tcc tca gcc agc atc gaa 3985 Met Met Glu Gly Arg Val Gly Arg Ala Ile Ser Ser Ala Ser Ile Glu 1315 1320 1325 ggt ctc atg ggc cgt gcc atc ccg ccg gag cga cac agc ccc cac cac 4033 Gly Leu Met Gly Arg Ala Ile Pro Pro Glu Arg His Ser Pro His His 1330 1335 1340 ctc aaa gag cag cac cac atc cgc ggg tcc atc aca caa ggg atc cct 4081 Leu Lys Glu Gln His His Ile Arg Gly Ser Ile Thr Gln Gly Ile Pro 1345 1350 1355 1360 cgg tcc tac gtg gag gca cag gag gac tac ctg cgt cgg gag gcc aag 4129 Arg Ser Tyr Val Glu Ala Gln Glu Asp Tyr Leu Arg Arg Glu Ala Lys 1365 1370 1375 ctc cta aag cgg gag ggc acg cct ccg ccc cca ccg ccc tca cgg gac 4177 Leu Leu Lys Arg Glu Gly Thr Pro Pro Pro Pro Pro Pro Ser Arg Asp 1380 1385 1390 ctg acc gag gcc tac aag acg cag gcc ctg ggc ccc ctg aag ctg aag 4225 Leu Thr Glu Ala Tyr Lys Thr Gln Ala Leu Gly Pro Leu Lys Leu Lys 1395 1400 1405 ccg gcc cat gag ggc ctg gtg gcc acg gtg aag gag gcg ggc cgc tcc 4273 Pro Ala His Glu Gly Leu Val Ala Thr Val Lys Glu Ala Gly Arg Ser 1410 1415 1420 atc cat gag atc ccg cgc gag gag ctg cgg cac acg ccc gag ctg ccc 4321 Ile His Glu Ile Pro Arg Glu Glu Leu Arg His Thr Pro Glu Leu Pro 1425 1430 1435 1440 ctg gcc ccg cgg ccg ctc aag gag ggc tcc atc acg cag ggc acc ccg 4369 Leu Ala Pro Arg Pro Leu Lys Glu Gly Ser Ile Thr Gln Gly Thr Pro 1445 1450 1455 ctc aag tac gac acc ggc gcg tcc acc act ggc tcc aaa aag cac gac 4417 Leu Lys Tyr Asp Thr Gly Ala Ser Thr Thr Gly Ser Lys Lys His Asp 1460 1465 1470 gta cgc tcc ctc atc ggc agc ccc ggc cgg acg ttc cca ccc gtg cac 4465 Val Arg Ser Leu Ile Gly Ser Pro Gly Arg Thr Phe Pro Pro Val His 1475 1480 1485 ccg ctg gat gtg atg gcc gac gcc cgg gca ctg gaa cgt gcc tgc tac 4513 Pro Leu Asp Val Met Ala Asp Ala Arg Ala Leu Glu Arg Ala Cys Tyr 1490 1495 1500 gag gag agc ctg aag agc cgg cca ggg acc gcc agc agc tcg ggg ggc 4561 Glu Glu Ser Leu Lys Ser Arg Pro Gly Thr Ala Ser Ser Ser Gly Gly 1505 1510 1515 1520 tcc att gcg cgc ggc gcc ccg gtc att gtg cct gag ctg ggt aag ccg 4609 Ser Ile Ala Arg Gly Ala Pro Val Ile Val Pro Glu Leu Gly Lys Pro 1525 1530 1535 cgg cag agc ccc ctg acc tat gag gac cac ggg gca ccc ttt gcc ggc 4657 Arg Gln Ser Pro Leu Thr Tyr Glu Asp His Gly Ala Pro Phe Ala Gly 1540 1545 1550 cac ctc cca cga ggt tcg ccc gtg acc atg cgg gag ccc acg ccg cgc 4705 His Leu Pro Arg Gly Ser Pro Val Thr Met Arg Glu Pro Thr Pro Arg 1555 1560 1565 ctg cag gag ggc agc ctt tcg tcc agc aag gca tcc cag gac cga aag 4753 Leu Gln Glu Gly Ser Leu Ser Ser Ser Lys Ala Ser Gln Asp Arg Lys 1570 1575 1580 ctg acg tcg acg cct cgt gag atc gcc aag tcc ccg cac agc acc gtg 4801 Leu Thr Ser Thr Pro Arg Glu Ile Ala Lys Ser Pro His Ser Thr Val 1585 1590 1595 1600 ccc gag cac cac cca cac ccc atc tcg ccc tat gag cac ctg ctt cgg 4849 Pro Glu His His Pro His Pro Ile Ser Pro Tyr Glu His Leu Leu Arg 1605 1610 1615 ggc gtg agt ggc gtg gac ctg tat cgc agc cac atc ccc ctg gcc ttc 4897 Gly Val Ser Gly Val Asp Leu Tyr Arg Ser His Ile Pro Leu Ala Phe 1620 1625 1630 gac ccc acc tcc ata ccc cgc ggc atc cct ctg gac gca gcc gct gcc 4945 Asp Pro Thr Ser Ile Pro Arg Gly Ile Pro Leu Asp Ala Ala Ala Ala 1635 1640 1645 tac tac ctg ccc cga cac ctg gcc ccc aac ccc acc tac ccg cac ctg 4993 Tyr Tyr Leu Pro Arg His Leu Ala Pro Asn Pro Thr Tyr Pro His Leu 1650 1655 1660 tac cca ccc tac ctc atc cgc ggc tac ccc gac acg gcg gcg ctg gag 5041 Tyr Pro Pro Tyr Leu Ile Arg Gly Tyr Pro Asp Thr Ala Ala Leu Glu 1665 1670 1675 1680 aac cgg cag acc atc atc aat gac tac atc acc tcg cag cag atg cac 5089 Asn Arg Gln Thr Ile Ile Asn Asp Tyr Ile Thr Ser Gln Gln Met His 1685 1690 1695 cac aac acg gcc acc gcc atg gcc cag cga gct gat atg ctg agg ggc 5137 His Asn Thr Ala Thr Ala Met Ala Gln Arg Ala Asp Met Leu Arg Gly 1700 1705 1710 ctc tcg ccc cgc gag tcc tcg ctg gca ctc aac tac gct gcg ggt ccc 5185 Leu Ser Pro Arg Glu Ser Ser Leu Ala Leu Asn Tyr Ala Ala Gly Pro 1715 1720 1725 cga ggc atc atc gac ctg tcc caa gtg cca cac ctg cct gtg ctc gtg 5233 Arg Gly Ile Ile Asp Leu Ser Gln Val Pro His Leu Pro Val Leu Val 1730 1735 1740 ccc ccg aca cca ggc acc cca gcc acc gcc atg gac cgc ctt gcc tac 5281 Pro Pro Thr Pro Gly Thr Pro Ala Thr Ala Met Asp Arg Leu Ala Tyr 1745 1750 1755 1760 ctc ccc acc gcg ccc cag ccc ttc agc agc cgc cac agc agc tcc cca 5329 Leu Pro Thr Ala Pro Gln Pro Phe Ser Ser Arg His Ser Ser Ser Pro 1765 1770 1775 ctc tcc cca gga ggt cca aca cac ttg aca aaa cca acc acc acg tcc 5377 Leu Ser Pro Gly Gly Pro Thr His Leu Thr Lys Pro Thr Thr Thr Ser 1780 1785 1790 tcg tcc gag cgg gag cga gac cgg gat cga gag cgg gac cgg gat cgg 5425 Ser Ser Glu Arg Glu Arg Asp Arg Asp Arg Glu Arg Asp Arg Asp Arg 1795 1800 1805 gag cgg gaa aag tcc atc ctc acg tcc acc acg acg gtg gag cac gca 5473 Glu Arg Glu Lys Ser Ile Leu Thr Ser Thr Thr Thr Val Glu His Ala 1810 1815 1820 ccc atc tgg aga cct ggt aca gag cag agc agc ggc agc agc ggc agc 5521 Pro Ile Trp Arg Pro Gly Thr Glu Gln Ser Ser Gly Ser Ser Gly Ser 1825 1830 1835 1840 agc ggc ggg ggt ggg ggc agc agc agc cgc ccc gcc tcc cac tcc cat 5569 Ser Gly Gly Gly Gly Gly Ser Ser Ser Arg Pro Ala Ser His Ser His 1845 1850 1855 gcc cac cag cac tcg ccc atc tcc cct cgg acc cag gat gcc ctc cag 5617 Ala His Gln His Ser Pro Ile Ser Pro Arg Thr Gln Asp Ala Leu Gln 1860 1865 1870 cag aga ccc agt gtg ctt cac aac aca ggc atg aag ggt atc atc acc 5665 Gln Arg Pro Ser Val Leu His Asn Thr Gly Met Lys Gly Ile Ile Thr 1875 1880 1885 gct gtg gag ccc agc aag ccc acg gtc ctg agg tcc acc tcc acc tcc 5713 Ala Val Glu Pro Ser Lys Pro Thr Val Leu Arg Ser Thr Ser Thr Ser 1890 1895 1900 tca ccc gtt cgc cca gct gcc aca ttc cca cct gcc acc cac tgc cca 5761 Ser Pro Val Arg Pro Ala Ala Thr Phe Pro Pro Ala Thr His Cys Pro 1905 1910 1915 1920 ctg ggc ggc acc ctc gat ggg gtc tac cct acc ctc atg gag ccc gtc 5809 Leu Gly Gly Thr Leu Asp Gly Val Tyr Pro Thr Leu Met Glu Pro Val 1925 1930 1935 ttg ctg ccc aag gag gcc ccc cgg gtc gcc cgg cca gag cgg ccc cga 5857 Leu Leu Pro Lys Glu Ala Pro Arg Val Ala Arg Pro Glu Arg Pro Arg 1940 1945 1950 gca gac acc ggc cat gcc ttc ctc gcc aag ccc cca gcc cgc tcc ggg 5905 Ala Asp Thr Gly His Ala Phe Leu Ala Lys Pro Pro Ala Arg Ser Gly 1955 1960 1965 ctg gag ccc gcc tcc tcc ccc agc aag ggc tcg gag ccc cgg ccc cta 5953 Leu Glu Pro Ala Ser Ser Pro Ser Lys Gly Ser Glu Pro Arg Pro Leu 1970 1975 1980 gtg cct cct gtc tct ggc cac gcc acc atc gcc cgc acc cct gcg aag 6001 Val Pro Pro Val Ser Gly His Ala Thr Ile Ala Arg Thr Pro Ala Lys 1985 1990 1995 2000 aac ctc gca cct cac cac gcc agc ccg gac ccg ccg gcg cca cct gcc 6049 Asn Leu Ala Pro His His Ala Ser Pro Asp Pro Pro Ala Pro Pro Ala 2005 2010 2015 tcg gcc tcg gac ccg cac cgg gaa aag act caa agt aaa ccc ttt tcc 6097 Ser Ala Ser Asp Pro His Arg Glu Lys Thr Gln Ser Lys Pro Phe Ser 2020 2025 2030 atc cag gaa ctg gaa ctc cgt tct ctg ggt tac cac ggc agc agc tac 6145 Ile Gln Glu Leu Glu Leu Arg Ser Leu Gly Tyr His Gly Ser Ser Tyr 2035 2040 2045 agc ccc gaa ggg gtg gag ccc gtc agc cct gtg agc tca ccc agt ctg 6193 Ser Pro Glu Gly Val Glu Pro Val Ser Pro Val Ser Ser Pro Ser Leu 2050 2055 2060 acc cac gac aag ggg ctc ccc aag cac ctg gaa gag ctc gac aag agc 6241 Thr His Asp Lys Gly Leu Pro Lys His Leu Glu Glu Leu Asp Lys Ser 2065 2070 2075 2080 cac ctg gag ggg gag ctg cgg ccc aag cag cca ggc ccc gtg aag ctt 6289 His Leu Glu Gly Glu Leu Arg Pro Lys Gln Pro Gly Pro Val Lys Leu 2085 2090 2095 ggc ggg gag gcc gcc cac ctc cca cac ctg cgg ccg ctg cct gag agc 6337 Gly Gly Glu Ala Ala His Leu Pro His Leu Arg Pro Leu Pro Glu Ser 2100 2105 2110 cag ccc tcg tcc agc ccg ctg ctc cag acc gcc cca ggg gtc aaa ggt 6385 Gln Pro Ser Ser Ser Pro Leu Leu Gln Thr Ala Pro Gly Val Lys Gly 2115 2120 2125 cac cag cgg gtg gtc acc ctg gcc cag cac atc agt gag gtc atc aca 6433 His Gln Arg Val Val Thr Leu Ala Gln His Ile Ser Glu Val Ile Thr 2130 2135 2140 cag gac tac acc cgg cac cac cca cag cag ctc agc gca ccc ctg ccc 6481 Gln Asp Tyr Thr Arg His His Pro Gln Gln Leu Ser Ala Pro Leu Pro 2145 2150 2155 2160 gcc ccc ctc tac tcc ttc cct ggg gcc agc tgc ccc gtc ctg gac ctc 6529 Ala Pro Leu Tyr Ser Phe Pro Gly Ala Ser Cys Pro Val Leu Asp Leu 2165 2170 2175 cgc cgc cca ccc agt gac ctc tac ctc ccg ccc ccg gac cat ggt gcc 6577 Arg Arg Pro Pro Ser Asp Leu Tyr Leu Pro Pro Pro Asp His Gly Ala 2180 2185 2190 ccg gcc cgt ggc tcc ccc cac agc gaa ggg ggc aag agg tct cca gag 6625 Pro Ala Arg Gly Ser Pro His Ser Glu Gly Gly Lys Arg Ser Pro Glu 2195 2200 2205 cca aac aag acg tcg gtc ttg ggt ggt ggt gag gac ggt att gaa cct 6673 Pro Asn Lys Thr Ser Val Leu Gly Gly Gly Glu Asp Gly Ile Glu Pro 2210 2215 2220 gtg tcc cca ccg gag ggc atg acg gag cca ggg cac tcc cgg agt gct 6721 Val Ser Pro Pro Glu Gly Met Thr Glu Pro Gly His Ser Arg Ser Ala 2225 2230 2235 2240 gtg tac ccg ctg ctg tac cgg gat ggg gaa cag acg gag ccc agc agg 6769 Val Tyr Pro Leu Leu Tyr Arg Asp Gly Glu Gln Thr Glu Pro Ser Arg 2245 2250 2255 atg ggc tcc aag tct cca ggc aac acc agc cag ccg cca gcc ttc ttc 6817 Met Gly Ser Lys Ser Pro Gly Asn Thr Ser Gln Pro Pro Ala Phe Phe 2260 2265 2270 agc aag ctg acc gag agc aac tcc gcc atg gtc aag tcc aag aag caa 6865 Ser Lys Leu Thr Glu Ser Asn Ser Ala Met Val Lys Ser Lys Lys Gln 2275 2280 2285 gag atc aac aag aag ctg aac acc cac aac cgg aat gag cct gaa tac 6913 Glu Ile Asn Lys Lys Leu Asn Thr His Asn Arg Asn Glu Pro Glu Tyr 2290 2295 2300 aat atc agc cag cct ggg acg gag atc ttc aat atg ccc gcc atc acc 6961 Asn Ile Ser Gln Pro Gly Thr Glu Ile Phe Asn Met Pro Ala Ile Thr 2305 2310 2315 2320 gga aca ggc ctt atg acc tat aga agc cag gcg gtg cag gaa cat gcc 7009 Gly Thr Gly Leu Met Thr Tyr Arg Ser Gln Ala Val Gln Glu His Ala 2325 2330 2335 agc acc aac atg ggg ctg gag gcc ata att aga aag gca ctc atg ggt 7057 Ser Thr Asn Met Gly Leu Glu Ala Ile Ile Arg Lys Ala Leu Met Gly 2340 2345 2350 aaa tat gac cag tgg gaa gag tcc ccg ccg ctc agc gcc aat gct ttt 7105 Lys Tyr Asp Gln Trp Glu Glu Ser Pro Pro Leu Ser Ala Asn Ala Phe 2355 2360 2365 aac cct ctg aat gcc agt gcc agc ctg ccc gct gct atg ccc ata acc 7153 Asn Pro Leu Asn Ala Ser Ala Ser Leu Pro Ala Ala Met Pro Ile Thr 2370 2375 2380 gct gct gac gga cgg agt gac cac aca ctc acc tcg cca ggt ggc ggc 7201 Ala Ala Asp Gly Arg Ser Asp His Thr Leu Thr Ser Pro Gly Gly Gly 2385 2390 2395 2400 ggg aag gcc aag gtc tct ggc aga ccc agc agc cga aaa gcc aag tcc 7249 Gly Lys Ala Lys Val Ser Gly Arg Pro Ser Ser Arg Lys Ala Lys Ser 2405 2410 2415 ccg gcc ccg ggc ctg gca tct ggg gac cgg cca ccc tct gtc tcc tca 7297 Pro Ala Pro Gly Leu Ala Ser Gly Asp Arg Pro Pro Ser Val Ser Ser 2420 2425 2430 gtg cac tcg gag gga gac tgc aac cgc cgg acg ccg ctc acc aac cgc 7345 Val His Ser Glu Gly Asp Cys Asn Arg Arg Thr Pro Leu Thr Asn Arg 2435 2440 2445 gtg tgg gag gac agg ccc tcg tcc gca ggt tcc acg cca ttc ccc tac 7393 Val Trp Glu Asp Arg Pro Ser Ser Ala Gly Ser Thr Pro Phe Pro Tyr 2450 2455 2460 aac ccc ctg atc atg cgg ctg cag gcg ggt gtc atg gct tcc cca ccc 7441 Asn Pro Leu Ile Met Arg Leu Gln Ala Gly Val Met Ala Ser Pro Pro 2465 2470 2475 2480 cca ccg ggc ctc ccc gcg ggc agc ggg ccc ctc gct ggc ccc cac cac 7489 Pro Pro Gly Leu Pro Ala Gly Ser Gly Pro Leu Ala Gly Pro His His 2485 2490 2495 gcc tgg gac gag gag ccc aag cca ctg ctc tgc tcg cag tac gag aca 7537 Ala Trp Asp Glu Glu Pro Lys Pro Leu Leu Cys Ser Gln Tyr Glu Thr 2500 2505 2510 ctc tcc gac agc gag tga ctcagaacag ggcggggggg ggcgggcggt 7585 Leu Ser Asp Ser Glu 2515 gtcaggtccc agcgagccac aggaacggcc ctgcaggagc ggggcggctg ccgactcccc 7645 caaccaagga aggagcccct gagtccgcct gcgcctccat ccatctgtcc gtccagagcc 7705 ggcatccttg cctgtctaaa gccttaacta agactcccgc cccgggctgg ccctgtgcag 7765 accttactca ggggatgttt acctggtgct cgggaaggga ggggaagggg ccggggaggg 7825 ggcacggcag gcgtgtggca gccacacaca ggcggccagg gcggccaggg acccaaagca 7885 ggatgaccac gcacctccac gccactgcct cccccgaatg catttggaac caaagtctaa 7945 actgagctcg cagcccccgc gccctccctc cgcctcccat cccgcttagc gctctggaca 8005 gatggacgca ggccctgtcc agcccccagt gcgctcgttc cggtccccac agactgcccc 8065 agccaacgag attgctggaa accaagtcag gccaggtggg cggacaaaag ggccaggtgc 8125 ggcctggggg gaacggatgc tccgaggact ggactgtttt tttcacacat cgttgccgca 8185 gcggtgggaa ggaaaggcag atgtaaatga tgtgttggtt tacagggtat atttttgata 8245 ccttcaatga attaattcag atgttttacg caaggaagga cttacccagt attactgctg 8305 ctgtgctttt gatctctgct taccgttcaa gaggcgtgtg caggccgaca gtcggtgacc 8365 ccatcactcg caggaccaag ggggcgggga ctgctcgtca cgccccgctg tgtcctccct 8425 ccctcccttc cttgggcaga atgaattcga tgcgtattct gtggccgcca tttgcgcagg 8485 gtggtggtat tctgtcattt acacacgtcg ttctaattaa aaagcgaatt atactccaaa 8545 aaaaaaaaaa aaaaaa 8561 12 221000 DNA H. sapiens unsure 77967 unknown 12 ctgtctgctg ttggactgac tggctcatat tgatttgtgg gtgtcccctc tgtattctgg 60 gtactagcta tcattgcact acttttgact ttgtatggta actcagaaat tcttaaatga 120 ggctgggcac agtggctcgc acctgtaatc ctagcacttt gggaggccaa ggcaggagga 180 ttgcttgagc tcaggagttt gaaaccagcc tgggcaacat ggtgagaccc tgtctctaca 240 aaaaaataca aaaattagcc gggcatggtg gcacgtgccc atagtcccag ctacttagca 300 ggcttaggtg ggaggatcgc cttagggttg gggctgcagg gagccatgat tgcaccccag 360 cctgagtgac agagcgagac tatatccaaa acaaaaacaa aaacaaaaac actccaaaat 420 accaaacaaa caaaaataaa ttcttgcatg agaatagtag acacccccac ccccggaccc 480 catccttcag gtgtccgtcg acccatctcc ctgtttgtgg ggtcctctgg gtagttaatg 540 gggcagtttc ccagtagcct agccgtgtgg cccggggccc ctcggtggtc ttgccagggt 600 gtgtgggatg cctttaaacc cacacatctg ggattgaatc acagctccgt cacttcccgg 660 ctctgagaac ctgggcatga gatttgattg tctgagcgtc agtctccctc tctgtcaaat 720 aggtagcagt acctgcctca cagggttctc atggagaaat acttggccca gtgcttacga 780 cacatgggcc ctgacggcag acatggtctt ttttcctgca tgtcggtgtc gtcatgccaa 840 actgcataca tgcgatgtca actaacaaaa cccgtgtttt gtctgcaggt ctccctgagt 900 ctttgaggac acagcctcgc tggaggcagt ttctggtagg ttcatgtctg tctccacttg 960 gtgtccccag gaggttcatc ctgcctggac tttctcacgg gaagtgggtc tggaattact 1020 cggagccagg ttcggcctgg agtgtgtggt gggggcctcg gggggcgtgt ggggtctggc 1080 acatcagagc tgtccagggc agggagcaac ttagggcagt ttgcggggtc ccccagtgat 1140 gggccgtttc ctggctgagt tggtgcagtg attttttgat gacacctgag aggtgggagg 1200 gtccctgaca gtgtcagtgt caggagggtg ggcttccccg ggctccgggg ttcttggtca 1260 cattgctttt gtgctttggc ggtgggcccg caggtttggc cagggtgggg cctgtcgatg 1320 ggcccaggtg ttcgggtgtt gggtgctgga ggaagccctg aggctgaacc accactgtgg 1380 tccccgtgcc tagcaggcaa agaggtggcc tgggtcctgg tcttatcact gctacttctg 1440 tgctgggcac tggggccagg ttgctttatc tctctgtatc tctgtttctc catctgtaga 1500 ctgggcgggg aggcaataac agtttcccct tatagggttt tgctgcggtg attaatgctc 1560 atagagagca gtgcctggcc tgagaaggtg cctggtgagt cataatcaca ggtcgtgctt 1620 ttcacaggtc accccatttt gtgaccctca cagcaacact ccagaatggg tggtgcctca 1680 ttttacaagt ggggaaactg aggcacaggt tggtcacctg tcccagatct ttcagctgga 1740 agcaaagagc cagaagcaaa gaaccccttc tcacccttcc cagggaatgc agcaagtttc 1800 tcctggagtg ctcatttccc agccaggcag atggtcgctg agggcattgc agggctcgtg 1860 cgcatggagg ctggggcaca tggcgggcac acagcgtgtt ctggctcatg acaggctgtt 1920 gtcgggagat ttcattcttg ttccaaatac agtcatgtgc tgcataacga cattctggtc 1980 aacgatggac cgcatatatg acagtggtcc cataagatta taataccaca tttttttttt 2040 tttcgagaca gagtcttgct tggttgccca ggctggagtg cagtggtgtg atctcggctc 2100 actacaacct ctgcctccag gttcaagcta ttctcctgcc tcagcctcct tagtagctgg 2160 gattacaggc gtgcgccacc acgcctggct aatttttgta tttgtagtag agatggggtt 2220 tcgccatgtt ggccaggctg gtctcgaact cctgacctca agtgatcctc ctgcctcggc 2280 ctcccaaagt gctgggatga caggtgtgag ccaccaagcc cagagaatac cacatttgta 2340 ctgttccttt tctgtgtttg gatacctagt gtaccactgg gttctagctg cctgtgggag 2400 tcagtccagc cacacgccgt acaggtggta gcctgggaac cgtcggctac accagggttg 2460 tccaatcttt tggcttccct gggccacatt ggaagaagaa ttgtcttggg ccacccagaa 2520 aatacactag cactaatgat agcggatgaa ctaaaaaaaa aaaaaaaatc acaaaaaggt 2580 ctcataatgt tttcagaaag tttacaaatg tgtgccaggc cacattcaaa ggcatcctgg 2640 gccggggttg gacgagcttg gatgacacca cacaacctgg gtgtaccgct ggcactgagg 2700 tctaggtttg tgcaagtcca cccccatcgt gctcccacag ccacggcacc agctcccgtg 2760 cgtttctcag aacgtgtccc cgtggttaag cagtacatga ctatatattc gtttatggaa 2820 tggctctttc taaagcacct actgtgtgcc aggctctgtt gtgggtgctg ggaatagacc 2880 tgtggacaag acggccaagc acctagtcct ccctgcgggg agacagacca tgaccaaaag 2940 tcagtaagtg cgacgcttag cgggtctctt ggtggtgagc accaggctga ggaacaagtg 3000 gtgaaggggt ctggggagcc tgtgggtggg ctgggggttg cagtttcaaa gtgggggtca 3060 gggtaggcct ccctgagaag gtggcctttg agcaaagacc tgaagtaggg gaggaaggaa 3120 gcatgtaggt atctggggga agggtgaccc aggctgaggg aacagccctg ccaaagcact 3180 gaggcagctt ggaatgggcc tcccgggttg cgcgattctg agttacctcg ggggagtttt 3240 cctggaggag gcctctttac ttcttcctga gcctttgggg gccccccact aggcaggagg 3300 gaagatcagc cctgcaggtc atctgcttcc tggggctggg ccttgggccc taagccctgg 3360 gcctcacaac caggttttgt cttggaggga gcaggggaag gaggattggg atttggaggt 3420 aggagaagga ggagtgggac tggggtgggg gaggaggagt gggatttgga gggaggaggg 3480 gaaggaggag tgcgatttgg aggtggggga aagaggagtg ggatttggag ggagggggga 3540 agaggagtgg gatttggagg gaggagggga aggaggagtg ggatttggag ggagggagga 3600 aggaggagtg ggatttgggt tagggagggg gaaggaggag tgggacttgg agggaggggg 3660 gaaagaggag tgggatttgg aggtggggga aggaggagtg ggacggtggc ggtcccccac 3720 aaagtgatga actcagcagg gctttctgcc taggctcatg gggctttgaa gttggaagga 3780 aagcggcctg gtctgggctg tttttcccag cctcctcctc ctctgcctcg ctgtcccccg 3840 tccatcggcg tctccgtctc cggcctaatg gggagccttc ctcctgtggc tgagttatct 3900 gcttgtcatg ccagtggccc acccgaggac gataaaaggg ctttttgtct gcaagcactt 3960 agcttcctct gccggggcga tccatcacat ctgagggagg ccgggaaggc agacagacgg 4020 tggagtgggg cctcctcctc ccctgctgag ggaacctgat gctcccagga gcccccttgc 4080 aggacccaag tggctcctca gcccgaaggc aaggcctgtc tgggggccag caggggtgag 4140 tgggagtggg gccatggggg cacattgagg caggcagatg ctctgcactc ccctgacaga 4200 ggacagacgc tgcccggatg ccctgcccca ccacacccac ttggcagctc tgtggggccc 4260 ctctgggacc ctccatgctg gagagggtgg gtggggggtg cagccttttc tgagtaagaa 4320 ccgtgatggt agaagggggc atgggggaga caagggggga cagacctcag ggccgacact 4380 cgctatgcgt gcactaagca ctttgtggaa ttacctcctt aaatctcagg gcgaccctgg 4440 aggtgggcac cgtccttatc cccattctcc agatgaggaa actgaggtac agggaggcga 4500 tgtggcatcc ccagggtgca gcagcagagg gagggcttgg ctccaggctc ccagcggtac 4560 actcttccct gcggacctag gaccttagaa gggggctgtg ggagcccctg gccccaaaag 4620 tgggttgccc gtgactcgaa actctgtgag tggattcttc agctgggagt ggggtgggga 4680 ggtgggtgtc tgggattgtc tatacattgg ggtgaggggt ccggtgtggg tgggggctgg 4740 ggtcacgggg taccctgggc gggtgatcgg ggacaccgaa ggtgtgtagg gggaggtttt 4800 agggccctgg cccagtggga tctcacctct cgggggctct gggaggaccg gctttaaccc 4860 cagttggacg gggccctggg ccctgcttgg gtggggagga gagcaattca gggccccctg 4920 cccttccctg tctgcgccac cacccttccc tctctgccat cctcctctct ctccttccca 4980 gcctggatgc tcagccctgg gcgggggctc cctgcaatcc cttcctcccc tcccccttcc 5040 ttcctgctcc ctacccctcc ttctcctccc tccttctccc cacaggccac cctcaaatga 5100 cagcaattaa tggtgcctgt gatggcgggc tgagaggagg aggctgacag ttgagcgtgt 5160 ctgcctgcgg ccgcccgcta atcgggcccg ggggatgccc ctcctgccgt tggctccagg 5220 cgcctgccct gccatcactc agaggggagc aggagccctg gacaggcctg tgggagctgg 5280 tgcagagccc ccatccctgc agccccctcc ctgtccttct attattatta tcattttctt 5340 tcataaacgg gtgggctctg gctggactct tgttcagcat gagttggtgg atgcctccca 5400 gacgtccttc tcctgaaatg acctctcatg tgcctgtgtt gtcctcaggg ccagccatcc 5460 ccacagggcc ccatcctttt gtccctgctt ccctgggaga ggcgggttgg gtggagccca 5520 ggaaccgtgt cctgtccgga cagcaggcat cagttaaatg ccccggcctg agtcctcggg 5580 gcctgggggc agctatttga gcccagagcc ttgtctggtg gggtgaggaa gtgtgttgtg 5640 tttgtcaggg ttacaagaat cctggccagc tctgtccaca gtgggcctgg gcttgaccat 5700 ttatcacctg gcagcagcaa taatgaagcc cctgctgtat gctggggcct gcagctggta 5760 tgttcacttt ggttcatttt acttggcagt tttctgagga gtgtggtatt tctcaccttg 5820 cttttgtaga gggggagact gaggggcaga gaggcaaagc gatttgccct aaggggcaca 5880 gtgccctacg tgacctagct agcataggac aaagctgggg ttcaacccag acccaaactg 5940 tccaatgctc atacatcagg ggactttggg aaacttgagg gccagtttag gaaccagcag 6000 actgatttag aagtgaggaa atagtccctg ggtactggga atggagtgag tagtgttaat 6060 atatgcatct ctctccctgt tccacttaag atcatcttca ttgagatgta attaacctat 6120 aatgatgcac ccattttaag ggttcaattg catgtgtttt gacaaatgta aacatttgca 6180 tcacctccac aatcagaata aagtgtttct gttcccccca aatccccacc agtcccttgg 6240 cactaaatct ctagcaccca cctccacccc ccacccccga ctagaggtac ccactgatct 6300 gctgttatag aagcttttaa ctcttctaga attttataat aaaattatca ttttattata 6360 tactatactt tgttgtgtct ggcttctttc actctgcata acccatgttg ctcatgtatc 6420 aattcattct ttctcatggc taagtagtat ttcattctgt ggatatatta cagtttatcc 6480 attcatcagt tgatggacat caaagtttcc agtttttggc tattgggaat aaagctgctc 6540 tgaacattct tgtgtaagtc tttgtgtgaa catgttttct tttttcttat gtgaatatct 6600 aggcattggg ttgctaggtc acatggtaaa tgtgttattt tagtttataa gaaaccacca 6660 gctgttttct aaagtggctg tcccattttg catgcccacc tgcagtggat gagagttcca 6720 gttgctcccc atccttgtca gcacttgcta ctgtcaatct tttaatgtta gccgttccag 6780 gagaccctaa tgcacatgcg attacatttt tcagcttttg ctgccttttg ggcaaagctg 6840 tggttctgtg ttttgatttt atgtgtctgg ccagctggtg ggagtctaaa ggatggtggg 6900 agataatctc gtgtctgcca acgctagctc tgtgttttcc tttctagtct ttatgctgct 6960 gactgactgc ttctcgtccg gctgcagtgg ttgagaccac agtgcagtgc cggattgcac 7020 cagttgggtt gtttggggtt agttagctgt gagtgttgtt atttattttt ttatttttta 7080 ttttttttga gacagagtct tgctctgtcg cccaggctgg agtgccatgg catgatcttg 7140 gctcactgca acctccgcct cccgggttca agcgattctc ctgcctcaac ctcccaagta 7200 gctgggatta caggcatgcg ccaccacatc tggctagttt ttgtattttt tttttttagt 7260 agagacgggg ttttgccatg ttggccaggc tgttcttgaa ctcctgacct caggtcatcc 7320 acttactttg cctcccaaag tgctaggatt agtgagtgtt tttttttttt tttttttttt 7380 tgagtcggag tttcgctctt atcgtgcagg ctggagtgca atggcacgat ctcggctcac 7440 tgcaacctcc gcctcccggg ttcaagcaat tctcctgcct cagcctccct agaagctggg 7500 attataggca tgcgccacca cgcctggcta attttgtatt tttagtagag acggggtttc 7560 tctgtgttgg ccaggctggt ctcgaattcc cgacctcagg tgatctgccc gcctcggcct 7620 cccaaactgt tgggattaca ggcgtgagcc accgcgccca gaggtgttgt tcttaacact 7680 catcttacag atgaggaaac tgaggctctg acaggtcagg tgacttccat tccgataaga 7740 aatgaaactc atgactctga gttgtgtgcc ctttctcctc cttcaggcta ggaggtgcca 7800 gctccgtttg ttgcagtgat gtgtttgcca gtccagaggg tcatgccaag aattggtggc 7860 tggttggggc caggaccacc tttttcctag ggtttcctct gctggagaga tgagggtgtg 7920 gaggagacgc tgtgccttcc ggatcaagca ctgtcctttg gcactgagca ctgttgagtg 7980 aatgtcaggc gttggttctg ccaagggtct tccttgttca atcctgttgt cttgggcaaa 8040 accacacctg ccttccgggg agctattttg gggcaaggga ggagcatggc atatggaagc 8100 ccaggaatgg gctgggatgg aagagggggc ctccttctcc tttttccttg cctgaggggt 8160 gtcagctaag atgacttttc ggggaaggag gcctgtaaat taaataagca atcccgtaaa 8220 taaataagta atgaagtcag cggggtgcct aattacatca gattcatcat tgtggatgga 8280 tgcctgcccg gtcattgtac ttgtttttaa tcttcggctc tgacatgtgt ctccttccgt 8340 ctcatagtca tccccacccc agctggaggg aggaggcggg gaggcgctgc tgtaggggct 8400 tccagagagc cttggtggtg gaggtggtgg tggggtccct ggagggttat ttacccagtc 8460 tgcctgttta tggcagtcgt ggaagggatg acgtctgttc cacagtgaaa cctcaggagg 8520 cctcgggcca tcctgattca gcaaatccct catcaggctg cgctgaaggg tagatgacaa 8580 acatggtgcc ccgcacagat ggggccacag cacacgcagc acgccctgga gggcgagatg 8640 ggaaggacac ggacgggggc agatgacctc agtgcaaagt cccagggatc caggtggacc 8700 cgtctttatg ctgcagttgg gtttgtaaac ctactggagc ttcgaagtgg gagcacccca 8760 tggcagtgac agcagcagtc ctaacagggt ttgtgatcgt ccttgtgtca cacttcacat 8820 gttataattt atttaattga ctgggcacag tggctcacgt ctgtaatgta atcccagcac 8880 tttggaaggc cgaggcaggc ggatcatctg aggtcaggag ttcgagacca gcctggccaa 8940 catggtgaaa ccccgtctct aataaaaaca gaagaattag ccgggcgtgg tggcgggcgc 9000 ctgtaatccc aactactgga gaggctgagg caggagaatt gtttgaaccc aggaggcaga 9060 gactgcagtg agctgagatc gtgccactgc actccagcct gggcaacaga gcaagactcc 9120 acctcaaaaa aaaaaataaa taaaaaatta tttcatcacc taaaagctct tgtaaagtag 9180 ggattatcat catcccctct ttacatatga ggaaactgag gcacagagag gttccgcatc 9240 ttgcccgagg tcacacagcc agtgaacttt gcactcaagt catctgcccc cgtctgcgtc 9300 cttcccatct caccctacag ggcgtgctgt gtgtgctgtg gccgcgtctg tgcggggcgc 9360 cgtgtttgtc atctaccctt cagcacggcc tgttcaggga tttgctgaat caggatggcc 9420 tgaggcctcc tgaggtttca ctgctgaaaa gatctcatca tcccttccac gactgccata 9480 aacagatgcc attctgaact gtaaaataaa atcatgtttc actaaggaca aagcaagccc 9540 atttgctgaa attaaaatag cttctttcca gatcttctct ttctctttca gcggccctga 9600 ttggctggct cttgggggac tctctgtcct gcctgagata atggtcctta gacccattgt 9660 acagttggag aaactgaggc tcagggaggt ggaggagcat gagtgagacc acacagctgg 9720 gaggtggtga agctgggatt ctagctgctt cttactgttt ggtttgggga gcgggggcca 9780 cctcatgtgc ctgacgtgga aggggctgcc tgtcctctcc gagaagcgca gggagctgtg 9840 tgcaccccag gctggctttg ctggggttct tgctgtggct gattggttag cgtcctgtct 9900 gtccgcgggg gagaggagac cagctgcccc acctcgtggt ttctcctcag gacctgagca 9960 tgtgctgggc atggacagag gatgggggtg gctgggggca gtcttgtcct cgttcgctgt 10020 ccatgcagct ccagggtgcc cagccacagc ccacacctgt tccctccatg gtgcctctcc 10080 atatctccag actccaggtc ctgtacgagg cagtggggcc tgaacccttg ggatgtctgg 10140 gcctctactg ggggcccagg gagggaacac cctttacttt acagggtgta cttgtgcagc 10200 cggacagggc ctgcgttgct gggccgtggc ttggatggga gtgggggttc acacattccc 10260 ctggtgctga cttcaggctt gcggggtttg gggctctccc tgcccctcac tgtcacctgg 10320 ggtggagaga ggagttgagg aaagacccac atgaagaatt gtgtgtgtcc atggtgttcc 10380 tgggggttgg agcaatccaa ggaggctgcc tggaggagct ggaacactca cattgaataa 10440 tcataagccc atcttggagg gactaatgtg tgtacatgct tcaaacagga cctggcacag 10500 agcaaatacc atatttacca taaaagctaa catttcctga tccttttctt gcctcagtgc 10560 tgtgtgtgag ttgccagtat tattattatt aacattaact acaatttcta acgtgcaccc 10620 catacataca cgcatgtact ctttgcagca gccttagaag gtaggtgcta ttatgatcag 10680 ccctgttttc tagttaaggg gattgagggc agagagaggt taggggactt gtccaaggtc 10740 gcccagttgg cagagctagg atgtgaaccc agaacgcctg actccacggc agctgctttt 10800 catcgtgtgg atggtgcagg tgccacctgc agccctccct ctgccccgtg ggtacgccga 10860 tcactgccgc agccagcctg gatctcttgg cagggccatg ccagctgtgg gacagcctcc 10920 atgtgccacg tagggccctc aggcacgcag cagctgctct gggcagtgtg ggatggtcag 10980 gacgtgggac atctgcttcc tgcctccctg cagccagatt ggtgtcccca cggcctcctc 11040 ctggttgagg ggatggcaaa cagcaaacaa gatgcggcgc tttgccttat ggatcacaca 11100 ggctgatggg gagatgggca gtgccaaaaa acaaacacga ttttgcaagg caagaaaatg 11160 ctgcctgtga aataatacag ggtggggagg tagggatgac ttcagtttcg ggggactcat 11220 tttaggtaag aattccaggg tagcttctga ggaggtggca tctgagctgg gccctggaca 11280 ataaggaggc acccactatg tgaaaggaag ggggatgagg gaacagcagg cgcgaaggcc 11340 ctccggccac catgtttcag gcatgctgat tggggttctg tgcctcagtt tcccactctg 11400 taatggctgg agcagagcag gggggcccca ggagggcttt cctggatctg agactgtcct 11460 gcagacctcc agggctgggc tgtttttcac atttaaggca gaagtcaaat ttaatgactt 11520 ttgcctttcc cttttgttct tttgctccat agttaatttc catgtattta catggtttta 11580 atttacatgt attgggcacg tggcatgttc cggactcatg tacgtcactg ggatgagaat 11640 ggtggagaag ttggacattg cctgtgcctt cgagtttagt atccagaggg ggagtgtcag 11700 ttaaacaagc aagtgctatc gcgggtggtg agggttgtga ggacgaggtt caggcattca 11760 cctgggtgag gcaagagctg aattagtctt ccatcaggcc aggcgtccag ggacgagtca 11820 ttcaagggga gacctggggg tgattagtta ggggcagtta gttagggctc ctgagttgtg 11880 gcagagacac actcgagccg agttaggcta tgacggggag ttgatgggtc ctcagagtgg 11940 ccagggtagg acacgttcag gcacggctgg atctaggtgc tcaaacaatg cctctgggag 12000 ctggctttgc ctcagctgtg cctccttcca tgcgggcctt gttctcagac aggctcatgc 12060 caccagccca gcccagccag ccaaggagaa ggagagtcac ctggcatccc aggagggaca 12120 ctcctttctc ttgtttgagt gaggtcctcg acatttgttt cactgtttgc aacagcaaga 12180 ggaggtggcc aaagaaggga taaggggatg tcccaaactc agacacaggg aggaaaggag 12240 tgagtgagtc agtgcaggtc aaaggggagg agtggggatt gtggctaact ggcatgctgg 12300 gtattctgat ggttttccaa gagaagctgg aaatctggat tttataagga atggcctagt 12360 ttttaaaaaa cattgaatgg gccagaacaa gttttcttca tggccacaac tggctgtcac 12420 cattttatag cctcttctta gcagtgactt ttaaagtatt ttgtccccac tgtgatctgg 12480 gtagaatgtc ccatgggctg ttccagaagg tctcaagtct tgggaagtca cgtctgacac 12540 cattggagat gccatttctg aaagtcaagg cccacggcca cagcagtttc tcagagaaca 12600 ataccatgtc tccagtgggg cctgacattc ttggagacag tatagtctag tggttagtgt 12660 cgtagatgcg ggtttcacac ttgctgagtt caaaaccgac attgccactt cccagccccg 12720 tccccttggg caagtcactt cactgctctc tgcctcagtt tcccagtatg tattaatgga 12780 atgggtatga cagcacccca taggattgtt gtaaggcaag cttgtccaac ctgcggctca 12840 ggacggtttt aaatgcagcc caacacaaat ttgtaaactt tcttaaaaca gattgttttt 12900 cggttttttg tttttttttt ttttttagtt catcagctat ggttagtgtt agtgttatgt 12960 gtgatccgag acagttcttt tagtgtggcc cagtgaagcc aaaagactgg acacgccggt 13020 tgtaaggcac agtggaggcc gcgtgaagcc cactgaccct ggcacactga gagcttgagt 13080 gatgctggcc ggcgtgatgt gtccttcccg ggttaggtcc ctgggatcca gctggctggc 13140 gtggagcatt cctgggcact cctctttcct ctgccgctgc ccctgccacc ggggtgtggg 13200 ttcccaggag ccccagaaca ggcagccacc tgccccctgc ccccagccgt ccttgccagt 13260 tgctgggtgc ccatggtatt ctggcgtgcc ggatggtgct gcagttggaa gtgagtcttg 13320 agtgagcaat taactctgcc agctgccagc tcacagctgc tgtgggtggg ggcggcccct 13380 tttaaaaata aaaacaacat gcagaaaaac agccctggag taccgttggc ttcccttagc 13440 caacgtggtc agggcttcat tttgatgctt ttgtggagaa gaatcccggg cctggatggg 13500 gaaataggat gcattttggt ctggggagtg tctttattta ggggcagagg tgatggcctg 13560 tgtctggcct ccccatccag gaggcaggcc cctttcctca agctgcccac gagtggctgg 13620 ctcatggatg cctgccacag ggaaggggat ttgggttcct tggggccagt ttttagcagg 13680 ctcaggccgg agagggtggc tgtgggacct ctcaggtctg tttccagctc tgtcggctat 13740 aggggggccc tggggccatc ccggagatcc ctggagctct cctctgcagc ttccagccag 13800 ttttctggaa ctagcgggaa aggaaagggg caccaaaggt gtttccgggc atgcgactgc 13860 tgccactttg aggtcttggc tttggtagtg ggttgagtca tggcccatga aacataggta 13920 cacttggaaa ctgtgaatat gaccttggcc ttatttggac cacaggtctt cgcagatgtc 13980 actaaggtaa gggtctcaag atgggatcat cctggaatag gatgggccct aaatccaatg 14040 acaagtgttc taagagaaga cacacagcag agaagtccac gtgaagatgg aaggaacgcc 14100 aggagccact gggaactgga agacacagag aaggctcccc ctgcagagtc tttggagggt 14160 gtgtggccct ggtgacacct tgagcttgga tttctggcct ccagaactgt gagaggatag 14220 gtcgctggtt tcagccaccc aatttgtaat aatttgttat agcagccaca ggaaacgaat 14280 acagttgtga actttatttt aatcactcat gtattttaaa attaaaatgt aaaatgtaat 14340 tttgtcttgt tcactgccat atttccagtg ctcagcacat acagtagggg ctcagcagat 14400 gcttctcgaa tgtctgatag ctccaggcct gggtgaggaa ctcctacctg ctgggagttg 14460 gacccagctt tcaggaagtc ggtaaactgg gctggagtgg tgtgcattca gcaacaccat 14520 ctttttgttt atttatttgt ttatttgaga tgcggccttg ctctgttgcc caggctggag 14580 tgcagtggca tgatcttggc tcactgcagc ctctgcctcc tggttcaagc aattctctta 14640 cctcagcctc ctgagtagct ggaattacgg gtatgcgcca ccacacctga ctgaattttg 14700 tatttttagt agagatgggg ttttgccatg atagccaggc tggtcttgag ctcctggcct 14760 caagcgatcc actgcgcccg gcctatttat tttcagttga ggtgaaattc acatcacata 14820 taatttacca ttttaacatg aacagttcat gagttcttag tacaatcaca atgttgagca 14880 cccacccctt ctatccaaaa aatgtcctca tcaccccaaa aggaaccctg taccggtggg 14940 gtcactccac gttgccgcct cccgcagccc ctggcagcta ccaatctgcc ttctgcctct 15000 gtggacttac ctattttggg tatttctcct ggacggaatc gtgcactgtg ggttttggct 15060 tctttcactc cgcacaatgt gtttgaggtt gatccgtgtt gaatggtgtg agtccttcat 15120 tcctttatat ggcggaattc cattgtgtgg catacatcaa tagaaccatt tgatatctaa 15180 gtggcttttc agatgaggaa actgaggctg cccaggtcac ggagccctgg ggcccgggat 15240 tgaggaggtg cagatagcca gacgtgtctg gctcacggtg ctgtctcttt ctcctgcccc 15300 caccctgctc cactcgtatc tgtgcctggc caggaagcag cagtgtgtgg ggaggaagtg 15360 agtgggggtc tcttccagct ggagccggat gctgaagcgt agctgcggct gtgggtctgg 15420 atctggtcct cagagttctg gcccccacct cccccctggg ccccacacat gtagtttctg 15480 ttgacctggg ttgcgagaga ggcagcaggc aggagctccc ccattcgcca gctgagcctt 15540 ctgatgcctc gagaggctgg gggccttgcc tggggccact cagcttaagg tccccctgcc 15600 cctttccaga ccccctttgg cccaccgtcc tggcccctgt ggcctgcggt gaatcatatt 15660 ctggggggtc ttcaccgatc tttcccaccg tcaaagctct gctcagcaga cgggctccag 15720 gaagcggcct gtcggcagat tttggccagg ggatgctttt tcgaagtatg gaggggtggt 15780 cgccgtcgaa ggcttgcgtg atggggagtt cttttgctga gcagataacc agacactggc 15840 ttattctgaa tatgagtttg gttttggcca caggctctgt ctgggggctg ctgcctgtgg 15900 ctgtttctgg tgtttgatga tttgtggtct tcattaagtc actcaacaaa caatttgctg 15960 cggagtatct ggcggggaag gcacaggaag cagaacgagt ggccgtgaag agacatgccc 16020 agtgtcaaac ctgcccatag cacacagtcg ctctgagggg gtgggaggag ttaccgtgga 16080 ttccagggcc agcctttggc gaaggtctgg atgcaggtct gtgtccaaaa caaacaaaaa 16140 tgaacagaag gaggtggtga ggcctgactc ggccgctctc aggcaccgct tcctggtggt 16200 gtttgcatgg ggccagtttg gcctgggtgt catggtcccg cctggtcttg gcgacggtct 16260 gggcgggaag atggtgctgg atctttgggc taaaaatatg cccgtgcctt cctgtgcctc 16320 agtttcccta cctataaaag aaggcgtaag agtagcagaa tcccaccttt ggctttgggg 16380 caggtctacg gaaacccccc aggggtgttt cctggggaag gctagagggc cagctgttca 16440 caggagacat ctggcttcca ggggcctccg cagccactat gctcatcccc tcgtggccag 16500 tctgggcccc ctgccagtcc agtggccacg ggcccctgtc acaggcaaat ctggtcttag 16560 tcctgaaacc ctcctgtgac tccttgtggc tgaattacca cgtggatagc ggagacaagc 16620 caggcttgcc cagttcaagt cccagctcag ccactagctg ttgaccttgg gcaagtcacc 16680 taccctctct gggccagcct cctgctctgt ctgtgtgtgg cggctcaggg gcatacctgc 16740 ctatgctgcg gtggtgtgag gccagctggt gaaccagggg acccgcttag cacagtgctg 16800 ggcacacagt ccgagctgct gggctcggtg tgtgtggcca ctgttattgt tattaatatt 16860 attactctca agatgctcct gagagtaaaa aggatgacaa tgttattgct ggagttgaag 16920 gccaggccca gagtccatct gaccacttcc cctccactcc tattagctcc ctgacctcat 16980 cgtcaaactc tccccgcctc gcccctgcgc cccggccaca ccagccttct ctctgctttg 17040 acaacacacc cgcgtggtcc agcctccaga ccttcacatc tgccatgctt ctgccagggg 17100 tgccttcctc acatctgcac ccccagaccc ttgtcatcat gtgggctgct gtccagggac 17160 acattcttag gcccaactct tggctgctag gggcagggaa gtgaatctgg agaccctggt 17220 ggagcctcct ctgcctcctg ggagctccag cagcttcctc tggcgcctca tctctgcttt 17280 ccagagcact tggagaagca gagctcagcc tgccccttct acggatggaa agttgacacc 17340 cagagaagct cagacttgtc tctgagtcac acagctaatt gcagccaagg ttcagactcc 17400 tggctgacta ccaagccatc attgttggcc tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg 17460 tgtgtgtgtg tgtgtgtgtg tatgtgtgtg tgtattattt ggccacgtct tcttttctag 17520 gcctgtcacc gagatgaccc cagatcagaa tgccagtgtg agggggtcac gctttctttt 17580 cctaggatta aaaggaggac agaaatattt gcaagggaga gcctgctcct ctggccatct 17640 ggccctcggg acagaggacg ggggagggat gggccgaggc ctgggttcgg aaccaggccg 17700 gagccaaggc gccagagcta cgctcaggtt ggaggtgcag gtgcggctcg aagctggaca 17760 gtccgggctg ggaggaagcg ggttaaagtg ggagaagcgg ggctggagct ctctttcgcc 17820 tgccagcgag cgaagagccg agctataaaa aggcctcaca gtgtttcagc tcccgagtgt 17880 cggctggaag cccgccaggg ttaccatggc gatgaggaat tattacttac tgccaaggct 17940 gggagaaaaa gctcgtactt ttggcttcca aacaagagga gtggacttat gtaattccct 18000 gtgtttatag gcccagagtg gcagaggcga gaacggatcg ctggaggccc gacgtctcgt 18060 tcacggccca gccgtggggt caggcggccc cgcacttgtc gccggtgggc cttggcctgc 18120 ccgggtttgg ggggcatcgg gctgggagcc tggggggcct ggcctggccc tgcagggcct 18180 ccagggccgg gatgggagtc gtagtctcgc gggaaggtga ggccgccctc tggggccgcc 18240 cctctgcggg tgtcatcctg gaggaaggat gggtctgatg ttggctgtgg tgtgcctcct 18300 ggaagccggc agcacagcct gtgtgtgtgg actctgctgg cccgctggct ggcacttttt 18360 ttctttttct ttttttttct tgtgagagag ttacttcaag ttgtgtttgg agctgacgtg 18420 agcgaggttg gtcatgtgct cgggtaagag aagtcgccgg gcttggagtg ggcagggagg 18480 tgcagtgtgg ctgggtcacc ccggccgggg gaggtgggcg cagactgggg tggggggctg 18540 tggcctgcag gctctatgca ggggcgctga ttgggggccg aggaattcat ctggaaagag 18600 ccctagttct gtcgctggag gtggtggcca gggctggggg ctgagtggcc ggccgcaggt 18660 cagccaatgg gggcagctgg accctcccct ggcagcgcag tgttgtcggc cctgagctca 18720 gcgggatggt gggcagggct gtctcatcgg acgaagttgc tgcagtcacg gaaaagagcg 18780 ctcggaggcg ctggccgggc aggccggggt gaggcttctt ggccggcccg cgtgggaggg 18840 gacccgggtg ggcactgtgc tcctctcctt ggtgcacatc cggcgtccct gggggggagc 18900 atggcgagcc ttgggggctc agggggcttc tgttcccgga gttgacttca ggagggcatg 18960 tgatcgtggg cgctcccgag gctctgccct ggggctccgc ggtgggctca ggcaggggag 19020 agccaggtgc aggcagcgct gcagcccggc cccggcgccc ggctccccac cgaggtggcg 19080 cttggctcgg tgcccatgtc tggtttgaaa tcagcgccac cggcccaggc ttgcccaggg 19140 acttggcagc gaggagccgg gataaacact ggaaagttgg aagggcttcc cgagctcaca 19200 aggagccttt agttgcaaac cggggggatg agggagtgat ttgtcctgag gtctgggtgc 19260 gccgcggcca tagggaggtg gcgggaatgg ctcctgggga cctctgagcc caggctgggg 19320 aagggagggg gctgggcttc caggcaatgt tgctcctttg ccacagacct gggtttgagt 19380 cctggctccg tcctctctat gctgtgtgac cttgggcgtg ttgcctcccc tttgcagacc 19440 tcagtttcct cgtctgtaaa atggggcaca gtggggtcta cacaagcatg ggactgacgg 19500 gagaaggagc tgcagtttta gggggaacgc ggggcagact gcctgggttc ctgtcctggt 19560 tggacacttc ctggctgtgt gaccttgggc aagtcactta ctgtctctga gcctcagttt 19620 tcccatctgg caaatggaag ttgcatcttt ccccacctca taggctgtat ggcttaaggg 19680 agtgaatgaa acctgccttc tagctcataa taggctcaca gttgataatt cactggcact 19740 ttgttttctc gatgctgaca ataccggcac ctggtctgag ggtggggggc ccctgggatt 19800 tcagcatctc agggcgatgg tatttatgaa gttgtagtgg ccggactgag gttccagtcc 19860 tggctcgacc cctcaaggat ggtgtgacct tgggcaagtc ccggaatccc acagagcctc 19920 agtttccttg tcctttacca cagtggtagc actgcagcct gccggtgtgt ctcgggagag 19980 cctgagagaa gcctgaaggg gcccgcacag tgctggcctg ggtgggcctc cgtaattgta 20040 accacaaggt tggatttaag ttcgagttcc gtccattttt cttttcttct ttgcagagag 20100 ctctcatgtt ttgtagaaac ctgggtccag ataatgggag gtaggtcgag tgggtgcttc 20160 ccaggctctg cctttgtttg ggatccccag gtctcccccc atgcctgcct gttctgcccc 20220 gtctcccact cagcctgagc ccctccgtgc cagccctggg ccaggcaccc cccacagtgc 20280 ctggtgtggc ctggggactg gcgcgggagg gccagttctc ctgcagaagg tggcagccgt 20340 cctgtgtttg taagtgacac cggatgctgg gccagtgact ggctcagggc ctccgctctt 20400 gggccagcag gagccagtgg ggagttcccc gggcgtccag gccccccgca ccagctgccc 20460 gctgtctcat tgtcatgggg cctctcctgg gacctcgaga atggcctccg aaggcggggg 20520 ggttctcatc catgtcccct tgtcaccccc agggccttgg tgtccacttg ggttggccac 20580 agagctgtgt cgtggctgcc cctgaccttt gccaaagtcc tcagggactc gattttccta 20640 cccggtggag aagagtcctg ggtgaggttc agaacagaag tcagcaccag ggcctttgtg 20700 acgaggcagc tcagcatgga ctggttgtga tcactggagt ctgcacatgt gataagaaca 20760 catagaacta aatacgcgca cactcacaca tgcacacaca tacatgcaca ctcacgcaca 20820 cacccacatg tatactcaca cgcacacttg tgaacataca caccatacac acagtcacac 20880 gaacatgcac acgcatactc gcacactcac actcacatgc acacacactc atatgcacac 20940 tcacagtcgt gcacacacac ccatactcac atgcagacac ccacacagat acatgcgcac 21000 atgcacacac acactcacac aagtgagtgc attggaaact gctgcaatct gcatacggct 21060 ggctatatcc atgctgcctt cctagttatg atatggatga tgaattgtcg ttgtctcagg 21120 tttgtctcag gatgttattc ttgggggagg ctgggtgaag ggcacacagg atcctgggat 21180 cttgattttt tttttttttc cttttttgaa accgagtctc actccgtcac ccaggctgga 21240 gtgcagtgca gtggcacgat ctcagctcac tgcaaccact gcctcctgag ttcaagcgat 21300 tctcctgtca cagcctccca agttgctggg actacaggcg catgccatca agcccagcta 21360 atgtttgtat ttttagtaga ggactccccc atgaagctgg cctgtaactg agcttggtcc 21420 cttggacatc ccagggggtc caggcagagt ttgctttgtg cctcaggatc acagagggct 21480 ccagagcgtc ccaggctggg ggacacgtgg tgcctgcagg gcctgtgggg gcctcatgac 21540 tgagctgctg taagggtgtt cctgtcatca gagtggcgtg gtggaggctt gtgtcccgtg 21600 ggcatgggtc gtagcttagg gtctggagag atgggggtgg gatagggttt gggggcatcc 21660 agcctcatga gcctcttctt tgctgttctt tggggcccct gatcatgggc ctgcctcagg 21720 acctttgcac tggctataac cttttttttt tttttttttt gagacaaagt ctcactcccg 21780 caggctggag tgcagagctg tggccacctt tctttcaggt tcaagcgatt ctcctgcctc 21840 ctgagtagct gggactacag gcgcatacca ccatgcctaa tttttgtatt ttgagtggag 21900 acagggtttt gccatgttag ccaggctggt cttgaactcc tgacctcaag tgatccacct 21960 gcctcggcct cccaaagtgc taggattaca ggcatgagcc accacacccg gcctggctgt 22020 aacctcttct gggaacaccc tttcctgaga ccttcagcct ccctgatata ggcctctgct 22080 aatggcgcct cctgagagag gcctgatgtc agttgtgact ccctgtgaca ccttcactac 22140 tccttgtaac actgtcacca ccagggtctg cggtatgccc atcacccctg tccccacctt 22200 gttttagtct atttggactg ggtggctcac aaacaataga actttattgc tcacagttct 22260 ggaggctgga tgtccaagac caagatgctg gcagatttgg tgtcacatgg gacgagggcc 22320 cgtttcctgg ttcatagatg gtggcttctc ccaggaagag gggcagggcg gctttctggg 22380 ggcaccaatc ccactcatga cagctcatca cctcccagaa gccccacgct ctgacatcat 22440 cccgtggtga ttaggtctca acatgcagat tttgggggga cataaacatt cacactccag 22500 cacccctcca tccaggattt tgttcatctt tgtcaccgct gtgtccccag cactgggtat 22560 gtagcaggca cttaggagac agttgtgcct gactcagtgt cttccacggg gcctcagcct 22620 gtcccctccc cataaatggg gcctctctgg tgaaggaggc cctgcatttt ggggatgatt 22680 tggaaaacca ggaaaagttc tcatgctttt tctctgactg ccactggggt acccaccaag 22740 catcccaaga gagctacccc tcctagatac agtcatgaga aggaacccag ggatgctgta 22800 ggtacgggga gtgggggagg ggtggtgaca gcctcagcct tgtgtgttga ggaccaaggc 22860 gaggtgagca ttccacatac cttagttcat tgtgtccttc ccatagcctt gtaaagtcgg 22920 cacagagtca ccctctcctg ataaggcaca gagagggtag gcagcttgct caaagacaca 22980 cagctgcagg cctgcagtat taccaactga atggcatttc caaggcagtt gcttctttgc 23040 tcaaggtcat gcttagcatg ttaaggggat catcctgttt catccccaaa agtccctcta 23100 ctatccctat cttccgaggc gggtcctgtt ttctggggat ctggctcaga actggcaggg 23160 acccgtttcc caggctgaga gagtgcgcct catttagccc agagcagagg cccagagatg 23220 cccacacttc tgaaggttgg gggtcagttt ccagtgtggc ttagaagtta gagggcagga 23280 ggggcacccc agagtggagg aactgccctc ttcctccgga gtcgttcatt tgcatgacaa 23340 tgagcccttt gttcctgagg ccagcctcct tcccaggcta ataacataat tcctggcctg 23400 tgatgtcata atgggccctt tctgtggctg gggtcagagg ctgggtgggc agctgtgtgg 23460 gctgggccag gcctgctaat aaccagggag gtggtgattg ccaggggcct gtgtgccaag 23520 ctgcctcctt ccagggtctc gctgagtcct cccgagagag cagcgggagg tgggatttgc 23580 tcccctgttg acactggagc aagctgagcc tccaggaagc cctccctggc cccaccgttt 23640 gtctggtccc cctcgatgag ctgcttcaag cttcttggcc tgtggagtgg gggtgactca 23700 ctgtcagttt ggccctcggc cgagaggcgt gggcgtgaga gtcccttgtt tcctgtaaac 23760 tggagggagg ccaataccca gcggctactg tgttggggcc actcggaaag ccaggttcaa 23820 accttggccc cacttggtcc cctgggcatc ggctgaactc cctgtgcctc cgtttccccc 23880 tctgcttcat ggggttccgc tggggcttgg gctcagagct aggcagggag tgagctttca 23940 ggaaatgggc aatgtcagaa aaggcggggg ctggtggagt ggggtgagtg gtgatacccc 24000 caagagttag gtccatgtcc tagtaaccca gcccctgtca gagagagacc gtatttgata 24060 aaagggtctt tgcagatgtg ttttgagatg agctcatcct gggttaccca ggtgggccct 24120 gaatccaaag accagtgtcc ttagaagaga cagaagagga gagagcaaga ctacatgaac 24180 tacaggaaga caaaggcaga gattggaggg ctgaagccgc aagccaagga atgcctggag 24240 ccaccagcat ctggaagagg cagaaaggag cctccctttg agcttctgga gggagtaggg 24300 tcctgctgac gccttgattt tggacttcca ggctccagaa ctgttagaga ataaattgct 24360 gtcgttggcc gggcgaggtg gctcatgcct atagtcccag cactttggga ggccgaggtg 24420 ggcgcatcac ttgagcccag gatttcaaga tcagcctggg caacatggcg agaccctgtc 24480 tctacaaaaa gcacaaaaat tagccggatg tggtggcggc ttgcctgtag tcccacgctg 24540 aggcaggagg atcaattgag cccaggaggt caaggctgca gtaagccatg attgtgccac 24600 tgcactccag cctggaccac agagtgagac cctgtcaaaa aataataaaa aaataaaaat 24660 aaatcactgt tgttttaagt ttcctggttt gtggtcattt ttatggcagc cctaggaaat 24720 gaacacagct ggcgacgcca gtctctggag gtgggggaac tggccctggc gggggttggt 24780 actgttcccc actccaagcc tgagggtgca ggacaagttt gggtggccga gaaccccttt 24840 gtgcctggga gtgcatgaag ccccattcgg ggagtctgga ctttccagga aggacgcctt 24900 gctcgaacct gcctttcttg ccgagaacca aatccacaag gccctagacc ccacctgccg 24960 cctgctgttc gctgtcccct cagacagccc tgctaagggg acaggaccca gaggcaggag 25020 gctctcggat tctaccccgg ctttgcccca ggccccggac gccctttccc cacgcgtctg 25080 gtgactcctg cagaacccgg gttgcactca tcccccagca agccccaggt ttgccgggtg 25140 cccttgacaa atggagaaac taggcccaga gagggcaggc tacttggcag aggccacaca 25200 gctccttagt ggcactgacg gccttacagt ctcgccacgg gggctggcac tggggcttcc 25260 aggagtgggg atcagagttc tcggccactt ggagacctgg agtggagctg gccggctgtg 25320 tggacctggg gtcagttacc tgatatttgg gacactcggc tgcctttgat ggacctggcc 25380 tggtgtaggt ggtaccccga aatctgggct ttaagcacac cctgtctgtg ctctcagcct 25440 cagtctctct gtttgcaaac tggtctttga gcttcagctc cacgtctgcg attttgctct 25500 tagcatgttc atgcattcag caaacattta ttgagcacct gccatgtgca gtgtgctggg 25560 actctggggg acacaaaggt gtgactcttg cttcatggat cttgtgtttg gggctgtggg 25620 gggagaggaa atgcagcagc acaggttgga gtccagattc cgggttctga tgagggaggt 25680 cacggagctg ggccgtgagg gaggtgagga tgtggccttt cgtctcctcc tgggcccggg 25740 gtggacagtg tgcagcaggc tctcaagtgg acatggagat gcccacagcc tgtccgcggc 25800 ggcccatggg cacctctggc tggcaggacc tggcctggtc ttgtgagcag ggacatggga 25860 tgggagggct gcaaggcctg gctccagcct ggtgggagag acaacagtct cctctaacct 25920 aagcagcagg catgggtatg ctggtgacag ggtcccagga cacagtgggt gagctggaca 25980 caggaggtgg ctcgcctggg tttgcatcca ggctgtgccc ttgttggctg tgtgaccttg 26040 ggcaagttgc tcggcctctc tgtgccagtc tctccagctg tagaatgggg atgataacag 26100 aatccctcac gggggcgctg tgaggaagga gttggtgcca ccaagtgttg tgttggggac 26160 tggctgtgcc agtggctgcg aggtgttccc tcccgtggct gctcagggca gcggcgtgga 26220 agatggaagt ggcatttgct catcttcccg ctgccctgct cctccctgtg caaatagcct 26280 cagtcttcca cctaggaaac gggagctgta acaagcacat ggccccatgg aggtcgggag 26340 gagaagcgga gctggggtgc atcagtgcct gtggggtggg ggcttggggt cgccacctgc 26400 tccagattga ggccttggct gcccccgagg cctggaacag ccacttgttt tacaacccag 26460 gaaactgaag gcctggcagg gatggcccca agacatgccc atgggtacag cccatgtggt 26520 ggctcctggc tgcagacaat gcctcttttt tctggcctgg cgggagcagc ccaggcttgc 26580 tcaacctggc ctaggtttat cagcacattt ggttctgcgg tgcggctagc agacattccc 26640 tccaagagag atcgtgatgt tcctccggaa accgaggtcc ggaggctcag gttactgtgg 26700 ggggcggccg tcggggggtg tgtctgcctc tgagaagtga cccagatcag agctgggctg 26760 tgctgggcag tgttcatctg caaagctgcc gcctgctctt tcacccatga gagccactga 26820 cagctcagga agggactggg agccacccac tttcccttca gggtgacaca ggacaggcct 26880 ctccctggct cctgcctggc cccttccccc tacactgagt ctggcctggg tctcccattc 26940 catttctctg gcctcttctt ggctggcttt ggacctgtcc tcacctacat ggataaggga 27000 cctagcgggt ggaagagatc tgattccagg gagatcctat ctgagagttt gtgttttagg 27060 agggttgcta tcttaggtct cttggttgca atggacagac tccctctgcc tcctgcattt 27120 agcacaaata gttcaagtaa ctaaaaaacc tcagagaagc ttcaggcaca gttgggtcca 27180 ggtgctcccc actttcagtc cctgttagcc tgagactaat aattgcagtt cagtagcccc 27240 agtggaagga cagcttcttg ttcccaatat tccagcaaat atcatgggaa tgagttttgt 27300 tgcctcagct tgagagttca gagttaagcc cccccccgcc ccccaccaaa gccagtgcca 27360 ctttggctgg agggctgggt cagcctccct gagaccccag gactgagggt gcaggggggg 27420 tggttgccca gggaaattgg ggtgtggcat gcacggagtg gggccgggtg ggcagagaca 27480 ctgtgtcttg ctccctgtgt tggagatggg gccaggttgg ggtccctgcc tggcctgcct 27540 ttcatggcca gtgtgtgtgt gtcccattgg ggtggagcag gtggcgccga tgagtcactg 27600 ggtaagtttc attcctgtta tatttaatag ttgagggcct cttgggtccc ccctccaagc 27660 cgttgctggc gctccacctc ctgtcccccc atcagcccgc ttcagctccc cagccttccc 27720 tcacctctct tgtggcgtcc agtgaccacg tcataagcca caggtcatgt cctggcagcc 27780 cctgggctgt atttggctgt cagactgatt tattgggttg gttttatagt cagtgttttt 27840 ttagaaatat cgggagatgt ctcaaaattg ggcttcttgg ctttgctgga aagatttgga 27900 tgccgtggac cccctgcccc acgtggaccc tgttccagca gggtctggaa catcaggaat 27960 gtttgggggc cacattcctg ggtctctgct cagtgttggc tggggctgag ctgcggtcac 28020 ccccttcctg cgggcccctc ccctcggcgt ggtgcctgcc tgggcccttg tgttccggca 28080 gggtcttggg tatctacagc tctcctcttg ctttttgtcc ctgcccttct tcgggtggat 28140 catccgatcc caggtagacg cttagcttca gccgtcgcca ctcctgggcg ctgaagcatt 28200 tgtttactgt ctgagctcct ggctgcaggg gccataggac cttttgggtt cttgatcact 28260 gtcccgtcat cagacattta ttgatcaatg cccctggggt aattgaatgg cccagatgcg 28320 tccacttctg agcattggac agagctgacg taaagtggat tcttcccgtt tagcctggga 28380 gcccaggcgg cagtggggtc ctcccatcca ggccctttgt ggtccagcct ggccacttgc 28440 tgggggctgg gatgggttgg ggaggcagga ggggaccctt gttgagtggg tgggctctgt 28500 cgccctggac gctgctgctg gcacagctat tcttagcagc agaaacattt gtcctcattc 28560 acatgtggtg gatgcctcca gggatctacc ctgaaatact agaggcgacc ccataaattc 28620 ctcagaaagc catccttgag ggcctgcgtg catggaggag aagcgggagg aggcgtttcc 28680 ggcagctgca cagctgtgga tgtgtttgcc agatgttgga ggcagggaag tcggtgggaa 28740 ccttgcggag gccgccttca cactcggggt ctgggcatgg acatgagcgg gtgggacaga 28800 gactgcagac tggtgggcag agagaagggc tctggccctg gcctcaagtt ttggggtcca 28860 ggggcccctc tgaagcagtc agcccttccc tgggccctgg ccttgaggcc acctgggttg 28920 gaggcagctg gcgaggggag agctcagctt atcgggcgct tccgagggat cagaggtgca 28980 agtcgctgcc cagccatgcc ctgtggccgt catggggtcc tgaggtgagg tgggccagag 29040 acaaggcctg gacgcatgct gcactcggct ctgagggcct gctgagtgcc ggggccactg 29100 gcaacacttt gccttttatg ggggcagcct gagcctttgg ggccaccgcg gaacaacaca 29160 agcacaacac tagcaatcag ggaggtctcc ctggaggagg tgttgtttaa ttttaaattg 29220 tggtagatac atataatgtg aaatttacct tcagccattg gtaagtagat aattcagtag 29280 tgttaagaat agccatattg tttagcaacc gatctccagc acttttcatg tggcaaaact 29340 gaatcgctat atctgttaaa cagtaactcc cccttcctcg ctctccccag cccctggtcc 29400 cagccatttt cctttttgtc tctatgaatt cagtgactct ggccacctcc tacgagtgga 29460 atcgcacagt gtttgtcctt ttgtggctgg cttctgtcac tcagcataat gtcaggagct 29520 gtgttccatg tagtctgggg ttgttggttc attcttagcc atgaagcaaa acggatgaag 29580 acccaggacc ccaaccccgt ccgcatcctt tagaaacccc aggtcccacc gcctctccag 29640 gtgctgtcca ggagctcagc cccagctcag ccacccagct ccctgagccc cactctggca 29700 tggcctccct ctctcctgcc gtcacagccc aggggcacgg ggttaagtgg tttgcccagg 29760 ttacacagct ggtgccagcg tctccctccc cactgcccag acagcagcct cctctctgac 29820 tcctcacttc cctctgcaga gaagattgct gttgggaagg ccagatggag gagatgggtc 29880 taatggaaaa cacgtccctc ctggggcgcc cggaacttaa tgaggaagag gcggcagaac 29940 caggcgtaat gtttgtgaag tacgcaagtg gggagggccg ctccccgtgc agggcttctc 30000 gggtggagcc acaggaacct ggagtgcagg gagggttcgt cctgctgtgg tttatctccc 30060 tctcttcctt ttaaaattaa atggaaacaa aaaaaaaagg aggggaggag gaagtgattt 30120 tgagcatact tcgccgtggc gggggagcag ggccgagctg gctgccgtcc agcggacagg 30180 aacgctccaa ttatattgga aacagtaacg ggcctcctcg gaggctccga ccaacgccac 30240 ttccctttct gttcactgag ggcgggcgcc tgggctggca gggccgtggg gagggccggg 30300 ggtttgggca cccgtatcct gactgtgtgg ccttgggcaa gtcagttcac ctttccgagc 30360 ctcagttttc tgatctgttc agtggggcga attgtgtttg gtgaatggaa ctggagcgtc 30420 tgctgcctct ggtgttagca tgagataaat gtggcctgga gtggaggtgg ggcctgcttt 30480 gcctggggtg aaggggtgca ggaatgggga agctgggggg cttgaagcag aatgtgggga 30540 atgatagagg ctttcccagt ggccgaggag cctctctaga ggaggggaga gatggggctg 30600 gtgctggggg tgggttttgc acctggccta ttttcccctg gaagcaggag caggacgtgg 30660 cactggggag acaggaataa tgggctgggg catttgggct cacttgagaa tcacaggctc 30720 ctcccagact cagtttgcct atctgcaagg cgaagatagc catagtgact ggcttggtta 30780 acatcatcgc catcacctcc ctccttcccc cgagtggtcg gcgtggcaga gggcagtaac 30840 agccacgctc tccttctggg ggctcttctg tgggccgaga actgcaccga gattcttgta 30900 gctctttttt ccagtgaatc tttccaagtg aagctcagag aggtcaggac ctcacccaag 30960 gtcacacagc tgtggaagtg gcggagttgg gatttggaat tgatcagcac gtgggagccc 31020 tttggaatgg cagtgtgtcc acaggaggtg gcttggttga gagggcactg actcgtttca 31080 gtgaccgagg ggctcagccc acagcctcca tagctcctgc tcctacaggt gcagcccaca 31140 gcctccatag ctcctgctcc tacaggtgcg gctaaaactg ccgaggagga gccctgcctg 31200 gtgggggaga cagcggtaaa caggtagctg tggcacaggg ggccgagtcc atgggagtgg 31260 cagggggagc gggccatggc accggggggc ccccttgggg ttgggggaag gttccaagga 31320 ggtgccagta gaggcaggag ctgaaggctc aggagaagac agactgaacc tgccccattg 31380 agtccaacca gccaggcagg gcatgtaaac aaaggtagct gagtaggagg ggacgtggca 31440 aatagggaaa gccgagccta tctggtgtag atagcctctg cccacttcca gccggccatg 31500 gctggaacct cagtttcccc tgtcaaacga ttttgtggta aaatacgtac aaaatatacc 31560 attttggcta tactaaagtg aacaattagt ttgcatttag gacattcacg ggttgtgcaa 31620 ccaccacctc tgtctaattc caaaacagtt tcatcctccc agaaggaaac cccaaaccca 31680 ttaaaccgtc actcccctct cctccctccc cacaacccct ggcagcctcg ggcctttgtt 31740 ctgtcctggg aatctgcccc tcctgtgaag ttaatggaat catgcagtgc gtggcctttc 31800 tgagcggctt ctttgccttt tgtgccatgt cttcagggct cacctgcgtt gtggctgagt 31860 cagcgcttac ctttgcgtgg ctgaatcgta gtccattgat ggacagactg cgtttgtttc 31920 atctgtttgt cagtagatgg acatttgggt tgtttctgct tgttggctga tgtaaatagt 31980 gctgctgtgg gcattctaat cctttctgtt tgttttgtca ccagttttcc gttccttggg 32040 gatgtgtagc taggagtggc atcgctgggt catggggtaa ttctgggttt aacctagtga 32100 ctgttttcca cagtggctgc actgcacatc tgacattccc acccgcaatg tgtgagcagc 32160 cctcattagg agaagccaga cattccaaat ttcctgtgaa atccctcttt ataagagctg 32220 gtctctgggg cttagctgag ctgaccctgg ggtgaggaag caagtcccag gaaactgccc 32280 agagggagca agtctgggac ctgacgagac gctccgggca ccccagcttt ctggctttaa 32340 cctggcccac gtatctctac cctgtacatc tacccggggt caaggaggag gattcccagg 32400 ctggagtcct ctcggccttt ctcctcgaac ccagctcaag gggaagatgt gctggtttat 32460 gctgaaaagg gagaagtggt gccaggtggg ggactcggga gagttgagac cctcccacgc 32520 tgagtctggg tttgggactg gaggcagttt tccctagggt ccttcttact cagcaggctg 32580 ggacttgggg agcagttata tgggtttggg ggttcctgaa ggcgacagtg cctttctgtg 32640 tccctcatgg agctgggcat gtgggagggc ctgggaatat tagcaggatg aagacatgct 32700 tggccctggg gattggttag aaatgtaaga ccagaaaaac ccggaaaatg aagcagctaa 32760 gttgatatcc atctggtgat gagtgtgtgc atccatccgc ccatccatcc atccatccat 32820 ccatgcatcc atgcatccat ccgtccatcc atccatccat tcgtctgtcc atccatccat 32880 ccatccatcc atccatccat ccatccattc acccgtccat ccatccatcc atccatccat 32940 tcgcccatcc atccatccat ccatccgtcc gtccgtccat ccatccatcc gtccatccgt 33000 ccgtcttcca tctatccatc catccattcg tccatccatc catccattca tctgtccatc 33060 ctctgtccat ccatccatcc atccatcaat ccatcatcca tccatccatc catcagtcca 33120 tgcatccttc ctcctttctc tatccatgca tgcattcatc catccatcct cctttcctcc 33180 ctcccttcct cctttctcct ccatcctccc atctctatcc ctcttccatc ttctccctcc 33240 atccagccac cccctgctga gcacctgggt ggggagtctg ccagttgggc cagacctgtc 33300 actgggtgtg ggccgtggtc agcagggcct tttgcctttt gtctgacttg gtcactgctg 33360 tagctgtgct tgtacagtgt ttgcacataa cagatgctga aataattctc taattgatga 33420 gaatgggtca gcaaccggag tttgggatgg gtttggcttg cctggtctca gctggagggc 33480 agaccgcacc cttgtgggtg gcacctggga ttgagctctt agtatttgac cctcagcccc 33540 tccggcagag ccaacgacag gctggggttg ggtacctggc tcttccttag ggagtggaat 33600 gacctttctg ccaagtgagg gccaaggagt ctggcctcat tcctgcaggc ctgccgctgt 33660 gcatgggtgg aggcccgttt ctctagggcc ctgacaatcg tggctgtcat cattcagggt 33720 tacaggggcc cttttacctg tgccccacac tcagacacct gtgcccagtg ctcctcgaca 33780 caggggcagc tacagtgtcc tttgaacaca gagacgccag aggcagactt gccacaggag 33840 accgcacgtc agccttgttt aaagtgcacc agctgtgtcc ttcctagctc ccttgcagtg 33900 aacaccccag ctttctggct atagccagaa agagtgacct cacatgcctt cgctcacccc 33960 actctcccca ttcaggcctc cctgctgtcc tcacacacca ggctcggtcc tgcctctggg 34020 cctttgcacc tgctgtgcct gctgtgtgga ctccctcctc tccccggcgc ctttgcataa 34080 aaggcacctc tggtgacgca cccctgactg cccactttca aaatgtaccc ccattccctg 34140 cctgccgcct cctggttctg tttttctcca tcgtgctaac accttctgcc atcctcttac 34200 tcccgtctca cctgctggaa tggcagcttc acgaggtggg ggatttggga tcagtaattc 34260 actgctgtat ccccagcacc tttcacacag taggtgctta acaaatcgtg gtagacagag 34320 tgagccacca ggccgggcag caggagctct ctcttcaccc ccttcctcat tggctgtggg 34380 ggcccctctg gactgggctg ggcgaggtgc acccttgcca cgtcccaccg gctttccgca 34440 tctcaggact cactccagag ctggattcct gagcatccgt tctgcgccag gagtcctgct 34500 gaaggtggcc atcagatact tggccagttc cccagttttt actgcacgcc agaaagtaaa 34560 cacccaaggt gtcaacagct cgacccctgg agctggcgct ccgcagcatc ttgtgcgcac 34620 atcccagaac tgctgtccca gagttccccc cgggccggct tctcctcggg ccagactggc 34680 tgcagtggtt ttgtttagta aatatttatt agatgcctac tgtgtgctgg gctctgggga 34740 tacagcagtg aacaaaacaa gtatttctgg agcacctcct gaagtaggta gtgttctccc 34800 ttaaggtacg tctgcgtgga acctgggagt gcggccttgt ttggaaaggg tttttgcaga 34860 tcacattagt taagatgagg tcacaaccgg ataggggagg gccccaaatc caatatgacg 34920 ggtgccctta gaagaagggg agacacagag acaggagatg cagtggaaag gctgcgtgga 34980 gatagaggca gaggatggca cgatgcatct acaagccagg gaacaccggg ggttgccggg 35040 gccaccagag ctggaggagt gaggaagtag gaagggcctc ccccagagcc cccagaggcc 35100 gtggggccct gatgacagct ggatatggac tcgaggcctc cagaacagtg agacaatcca 35160 tttctgttgc ttgaagccat gcagtctgtg gtggggcagc cgagggcgct aatacgcctc 35220 gtgtgtgcca ggtgccgtgc ctctcggtgg ctgtcacaca ataggtgctt attccacagt 35280 gagtggagca aatacctact gagcggtgag ggaggccgta tgtggctgag ctgcagggct 35340 cctggggcct gcctgtcttc gcagggccag gctgggacag tggaggcacg gcctgtgttc 35400 ccgccgtggt tccgcccacc ccaggggggc tttgtgcctt gggcttctca gagtatcaga 35460 gggttctgtc gagtgtgtgt gtgtgtgtgt gtgtgtgtgt gcgcgtgcac gcgtgcgcgc 35520 tcgtgccgtg ggcgctctct gcctggcagg ttggttttta atcccgaggc tcccccacct 35580 gccacaggtt cttccaatgt cagcacccat tagttcccag aacatttcag gcacgtgcgg 35640 cgcagagccc cgcgtgcctt tcatcctccc cacagcccgc ggctgagcgc tccgggcaca 35700 tcctgtagct cccacacctc caccagcccc cgcctgcccc tcaccctgag gctgtaattc 35760 caccctcccc aggtctgaac caggccgctc aagacacaga aaatctatgg aatgtgtctc 35820 ggtgtggcct catcctgccg gagctggaga ggaatgcagg ggtgggaggc cccatggaag 35880 cttccagggc ctcccggaaa ggcgcctctg cccggccagg tgggaagagg acacaggtgt 35940 ggtggtttct ggcatcactg cgttgctggc atgcacctcc gctgggcaga gtcattcagt 36000 gtgcacctac tgtgtgccag gcaccagaag gggctctggg tccagcagga ggcaaggcgg 36060 acagccagtc agagctcacg gcccgagctt tccgctgtgg atttggaaac cttaccaaag 36120 cccgcagtgg ccgggaacag ggaatgtggc ccacttggct tctgctgctg cccggcagag 36180 tgcagtgggg gcggggggca cttgtgtgtt tgctacctcc ttgcaggcat ggcccaggga 36240 cagacccctg cagccgtgca tggggagccc ctccacctgc ctgtgtggga tctgcagccc 36300 tcctccagct ggttcagggg ccagcagggg ccctggggct gtggttggtg gcttggatgt 36360 gcagaggcct gcttgggccc ttggtgtccc cgttgggtat cccggccacc tgagatctac 36420 aagtcccttg acctcaccca ggcaccgtct tgttctcctc ggaggcctga ccctcctgac 36480 tctgcatggc tgagcacctg ctgttcccca ggcacctctc ggtatgccac aggcacaggg 36540 tcctcgcagc gggcctgtgc agcgggactc ctgcagcgag ctgtttccgc ggcctgcaga 36600 gtcagcctcc ctcctgactt tcacccacct gcccatttcc ccttctctgt cgctgttgcc 36660 ctgatccccc agtgtcccct ctcttggaca tttgcaggag cctccccagg tctccctgat 36720 ccactcttgc tgtccccagt gcctgctcgt aaaacactga ccctttactc gcccccgcaa 36780 ccaccttctg tggctcccca ctgccctgag aacaaaatcc atccttaccc gggcccatgg 36840 ggccctgaat gactctgtcc ccacttcccc ccatattcac tcaatgaatt tctcaaacat 36900 aaacggcacc tgtgctcacc cccaggccct cgctcacccc tgggcctgtg ctcaccgcct 36960 ggcgggggct cacccccaag cctgcgctca ccccccaccg gctggcgctc acctccctgc 37020 tcttgctcag cggcgcctcc agctggagca ctctccatcc cctcgccttc accctctgga 37080 agttcttctt cctcgtatct cctggctctc cccagggctg ggcagagccc ctggcctgag 37140 accctccagg gcctggaccc cgctgggttc acaagaagtc cccagcgcta gcccggggct 37200 cagcagggac cacagtgtgt atgtaaataa atgaatgccg cccacccttt ctgaccccac 37260 cgcagccaga cgcagcggcg acatggggcg tttgtgtctg aattccccct ccagcccgga 37320 tccatcctca gaacctcctt tggccaggac cagatcctgg agaccctgga ggggctccct 37380 cgtcctctcc tgcccccatc tttgaggaaa tgatgtcatc attttttttg gcattcactt 37440 ccaaacctgc tgatgaaaag tcaaagctta tttttttccc tattcgcagt gctgcacacc 37500 cgcctcctct atcaagtttc aaaacctttg catcactgcc ctgtaaaacc ctgtaaccat 37560 tagcaggcct cattcctgcc tcaccctgcc ctcctggtag ccaccagtct cctttctgcc 37620 tcgtggatgt gcctgttctg gacatttcat atccgtggag tcaggcagtt cgtggccttt 37680 tgtgtctggc ctctttggtt cagcatgaca ttttctggtt atgtgtggtg taggacacag 37740 ccgtccttcg ttcctcttta tggctgagta atactccatc gtagggatgg actggaattt 37800 ttgctgggtc tgccttttgg ctgctgtaaa ttctgttgcc atgaacatgc ataccgtgtt 37860 ttgtttgagt ccctgtttcc agttcttttg ggtggatgcc tgggaatgga attggtgggt 37920 catatggtta ttctatgttt aaatttttga ggaaccgcca aaccgtttcc ctaacatttg 37980 ttttttttcg agttggcagg aaacgtggct caggtcggga ggggttggaa actgggtttc 38040 ctaagctcgt ggtgagtgag ggtggcacga ggttactgga gttgttccct gttcaggccc 38100 caccggcatg tgaggcgctg ggtggggggc tggtggggga accccttggt aggtgagggg 38160 ccgaggttcc agccccatgc tccggggtgg gcactgtgta aatcccaggc agtggaaagc 38220 cagccagcca gctgcggggc actttaggac ggtgtcaccc tccctggtct ctggtgcccg 38280 tgtgcaccat ggtaagcgtg tgccaggggc ctgtcacccc caggcagcat ctcactgggc 38340 aaaggaggaa agaaaagctg tgggtaaatg agacctctcg gccaccttgt gcaactcaaa 38400 atccaatagc aatttggaag ttgcccgtgg tgcccttgaa agaggggcag acctcgggaa 38460 cagcaccctg cagaagtgac ggccttatct cctccgagag accgggaact gtttagcacc 38520 tagagagaag ggaatagaat ttgctttgct gcatgagatg accagggtct gcagactttg 38580 agccgagctc tagcaggaag aattttagaa cagggctggg tcctggtggc cacagctgtt 38640 ctctctccca gggccagact cttgtttctg gctgcagaac ggatgtctca ttgctcttgg 38700 ggccgggcag ggctagctgt gccttgcctc cccatcatag cgtcactggt gactgggctg 38760 cagctgcatc attgacagtc ctggtgacag cagtattagg cattctggtt tgctgagcat 38820 ttactgtgtg ctgggagctg ctgagtgcct gctgtccgcc acccggcctt tcctggggtc 38880 cttgcaggag gacttaggca gtcggaatat gcacagacgt cttcatgtgt gtgggagtgc 38940 gtttgtgatt ccgatgcctt cctatttatt ccacatagta ctgggtttct gtatacctat 39000 gctgataata agcttctctt gtatgtaaag ttatgcctaa ctgaatgaaa gtgacaggcc 39060 cggggctaga cggctgtcgc ctgggtaatc tctataaaaa agtccctacg cgggggtggc 39120 acatgaatgt ctgatgttta gggaacactg tgtgtttgga ggttcagaga gggcaagtga 39180 cttgcccaag gccacgcagc ttagcgatgg tggagcggga cgtgttccca tgttcacggg 39240 aattgcgcca tacatcctgt ctcggggctg ggaaagccca cgcaggcagg accgaggtgg 39300 tggtagatgt gtcagtcttg gctccggaat tccttggctt ttctgtgttt gaaggatgga 39360 cagcagccag ttgaaggggt ggcctcctct gtgactcctt ctttccctgt gtgagcccga 39420 attcttggtg gcatgtgaca gaaacccagc ttgggctgcc aaagacaaaa cgtgcagaag 39480 gagtgccctg gctcccctaa tgaagtgagc aggcttcgac ctgcctccag ccaccatcgg 39540 acacaacctg ctcttaccgc cctttcgccc tgccttcctg ccggtgggcg tgggtctcag 39600 gcaggctcct gctgcatggt ggcccccaga gctccaggct ttcattccca gcttagatcc 39660 ccagcagaga gcacctttct cctggttcca gcagcaaaag tctcaaggca gattctcatt 39720 gactcctatt gggtcacagg ctcatccttg agacagtcac tggcccagaa gcatgcagga 39780 ctctgattgg ccaggaccgg gtcacatgac catccctggc acctggggag ggagggaggg 39840 tcaagtctac actaatgaga gatgaggtgg ggcctgggag gcagtcaggg cccccaacct 39900 taaccttcct cccaatgccc ctccacatta ggcctccaag ggctttcctg cttggagaag 39960 gacggttacc ctcttcaggt tgggggaggg ggtgttctga tgaaattgca gggctgggta 40020 tgctctgttt cccctcctga cccctgacct cgtgtggtgc agcctcagtc ctccgccact 40080 ggaggcccac atccaggcgc tgggtcccgg tgccagggtg catttccctc agctctgggg 40140 ggtgtgtgca attgtggggg tgctggagag ggctttgcat gaggcaggac ctgatggaca 40200 caccttttct gagggactgg ttcagggaga gtgtggaggg ggccttggtc tgggatggga 40260 ccctgttgta agcccagcag gtggcgtgga gctgtggctg gcggaggaag gggagaagcc 40320 ttgttggggg tggggggtgc ttaggggttt cctggcaaag gcagcttcgg agtaggggtc 40380 cccgtggctc ccttgctggg ccgtgtcttc tctgtggggc tgtttttcca tctgtaaagc 40440 tgctagcccg cttcgtgtta ttcctctggc gtggccacga gtagatcctc tcccgtggaa 40500 ggctccagta tctgccccag gagccgtttg gggtacctat ccctaggctg cagggcccga 40560 ctggctgtca ttctgccctt ggctcttcct ggtgtagccc tccatgtcct aatcccacct 40620 cctagtttgc atctggctaa cctcatatca gtcctgtccc atgtcatggt gtcagcctcc 40680 tgcacagggt catagccttg cccaggtcat gctgtggcct gtggcccgtg gcccgcctga 40740 gctggccctg gtccctgctg cccgggacag cggtgtgtga tgtccctgct gccggccgcc 40800 cctcctggga caggtgcttt ctgggaattc tgccctgtga cttagaaacc cgggggccat 40860 ggagtgaagt tggatgggct taggggggct gggagccatc tgggtggtgg tgagggcagc 40920 gcagagtccc tgtgcctgcc gggtgaaggc ctgggtgggg aggaggcctc tggtcccttg 40980 cgtggcttgc atggctcgga gggaccttga atgccatgcc tgtctccttg tgctcccgga 41040 gaacaggtga gtgtggcagt ggatggagga gggtccaggc aggcccctgg gtgctcgcgt 41100 gtcctcacgg gaccacagga acgactcggg gacctgtgca cggaggagcc agctgccccg 41160 tggctgatct tgtttttctt ttcttgtttt cccgcaggtg ccagtgacgg ggtggcccgt 41220 gagctgatga cgaggactgg cttttaatcc ttggtggtga ttaagagaaa gcttattggg 41280 gcctgggagc agctccccgc cgacccccac caccatgtcg ggatccacac agcctgtggc 41340 acagacgtgg agggccactg agccccgcta cccgccccac agcctttcct acccagtgca 41400 gatcgcccgg acgcacacgg taagggggtg cacatgtgtg cgcctggggc tacctttgag 41460 acccttcttc cattccactg agtcttcacc ccttcctttc tcctgggagc caggctcatg 41520 tggctctgag cctcccaggg cagaggggag gccgccacag agacccctgg tgtctgaagc 41580 cttttccaga atatctgata aaatctcttt gctcccattt taaagctggg aagatggagg 41640 ctggggccag gctgagctgg ggctctgccc tctctggact ggtagtggga ttggcacgcg 41700 aatgtggagc tcctgctgta ttcactttcc tgcagcctag cctcacctct gctcccccgc 41760 tgccgcagta ttgggtagga ttggggtggc ttccaggggg caagggggcc ggataggtca 41820 cagctcccct tccttcctgt cctcccgttc cgtgtgtatt caccttggtg cggctcgagg 41880 ctctgaggtg aggaggcccc acacaggttg cgtttctgcc tccctgacat gagggtccag 41940 ggtgctggct gtgtctttgg ggagcccgcc ctgtggccag ggcagatggc ttgccctggg 42000 agcaggtggg cctcgctgcc tgcccacatg tgtgccctgg tcgggtctcc taagccgcac 42060 cccaccccac cccacttccc agcgggggcc ccatttcctg cctcttctct cactgcatgg 42120 tgtggccagg acaacgggcc ttggtttcgc tcctttggca tttatggggt gcttgctgta 42180 taccatgtct ctgggtgttt gccaagcggc tttcagagtt gtgggcctcc cccttgtgac 42240 ctcctggctg ctgagtgagg ggatgtgagg cctggaggtc acagctggag tgaagctgac 42300 cctgccggcc accgtggggg tgcgtgtgtg cgtgtgtgtg tgtgtctgtc ctgcctggct 42360 ggtgtggtcc cctcttgtga gaaccagaaa ggaagctgtg tgggaggacg tttccatcag 42420 tgagcagaag gttttgcata taagctcact ggccctgcct gggggagtcc ctgacacagt 42480 ggcctcctgt aggttgggcc cctggggcgc tttgcagagt cagctgtcct cagtgggtgc 42540 gttgtggatc cctcttagga cggcagttcc ctgggcagag tcattgcatt ctcctgggcg 42600 gccctgtgaa agagcagctc acgctctcat cccacttcgc agatgaggag actgaggccc 42660 aagaggttaa atcacaggcc tcaggtgcga ttgccctaag tggggaggct gccacagcat 42720 cggggctcca agcttctgtg tccccccact cccccgtgcc tctatttatt gagcacctac 42780 tgcgtgcctg gggctaagga atagactccc agtgggaaat gattttatat tttgtcatca 42840 ttgtctttat ctgtcaccac caccaacaaa aagaagagct cttgttaact gagcacctac 42900 tatgggtcaa atgttgttca aagccctgag tgtatatggt tgtgtgcatt cccctgatca 42960 ccccagagtg ggactatcat gctctgtatt ttgtcaatgg gaaaatattt cacagggtag 43020 gaaactggac aagttacgta acctctctga gcctcagttt tgtcacccat aaagtggggg 43080 tactgagagt acctgtctcc tagattctca cgaggggtaa aggggatatg ccgaatgttc 43140 ttaagatggc gcctggctca gggccagccc gctctgtccg tttgctgctg ccgttccttg 43200 gtcttgttgc tgtacctgca gctgcccaga ggggaacctg cctgccctgg gggtgctgct 43260 ggcttctggt ttcttgtcct gtcctgtgga ggttcccact cttctcaacc gccctcaccc 43320 ggctcctagc cttggggagt cctcaggctg ctgtggcctc tgctctccca cccctcctgc 43380 cctttgcccc aactgggccc tcggggtcac tggctgaccc tagacacctc ccattcttct 43440 cctgctgggc cgtcagtgac gcaggatgtg ggtggacagg gccaagcgct caccgccccc 43500 tccaggcagg aggctgaggc cagggagtga gtggggccca gcctggcggc cacaggtgag 43560 aacatgtctg tccttgtgtg ggggcagcag gggccacctg tgtgtgctcc tccctggggg 43620 agctgcccca tatcggaccc tcctgcctca tggtagggct gcccatccag agaatcctgc 43680 ttgtctcttg aagggcagga ggaagagttc tgggcactct gaggagggcc ctgctgccct 43740 gggcatattg cagggtggag ccgctttctt gctgtgggtt ggaggtgagc tgggggctgt 43800 gatctggagg cccctccctg gaagcccctc agccctcaaa cccttcctgt ccttttaaag 43860 ggcaagaccc agttcgaaag atactacccc cttcctgagc tcctcatcaa gccacagaaa 43920 gacagatccc cccgggtaag gggacagtca gtggcgggaa cctggctgtc ctggttcctc 43980 gtacagtagc cgaggccatt ctgctgggat ccacgggatg cctcagtgac cttcccagat 44040 tcaggtcacc tccacgcata ctcccgacag gcctacctcc tgggacagct cctcctgtct 44100 ggagagtcct cttcctggtg ctttgggcac ggggctgctt tgatggcagg tcttccctgg 44160 agcctgtgag acctcagtgt ggcttcgaac cctctccgtg ttcagcttgc tgagtggcat 44220 tggcccgctc acagccacgt ggaacggcct cagtttcccc acctgcagta ccggtgtcct 44280 ggtgggtctg tgcatcggtg gcaatgtctg cacgcagcaa gcgcggggta gtcatctctt 44340 tcctcctgga agggtggcag gagacccaag cagggcctct tccccctggg gaaccacagg 44400 accgtggatg ccgagctggc ggtggaatgg tgcaggccgt ggaagccgct gcctctgcct 44460 gtgctctgcc ctggcgtcat ctgcgggctg ctggtgagtg attcccagca caaatgggag 44520 gcttcactta gttgggtgct tgcagacaga ggcctggacc ctgagaccat ggaaagcccc 44580 caggttccct gactcagcct cagccatgct ccaggcttct atatgcatca tccctgccct 44640 cccgcttcct acctgccgca tccctctgtg cctcattctc tccatcctca ggggcccagc 44700 ttctctccgt gacagtagca ggatcctatg actctccctg agggtcctgg ggaagcgagg 44760 gtctccaggg ttgagggtcc agtaacaaaa tgctcacagc ttttgttttc ccggagatca 44820 acgcctcctc ctctcctggc ctcctttcag gctttctgtg gcccagctgc attctgcctt 44880 cttcttcaag tcctctggga cccctgaaca ctcctgagct cctccagacc ttgggctaaa 44940 cgaatgggct aaaggaatgc agttaaaagc agggacacag agtctgaatc ccagcgtgac 45000 tcttttctgc tgtgtggcct tgggcaagtt acttaacctc tctatgccgc agtattgaag 45060 actggttcat agcaccggtt ctggagccag gttgcttgca tttacatcct gccccagtga 45120 tgtcctagct gtgaaacagg gggcaagtgg ccttaccgtc ccgtgcctca gtttccctat 45180 cagttgagca aggatagttt taagattgtg aggatccaat tagttggtag gtgcagagtc 45240 cttcgcacag ggtatggaca gagtaagcag acatttgata taatcaataa tgtaatgatg 45300 acgatgctat tattacaaca tcgcctttag tagctttttc tgtcttgccc caagggtaca 45360 ctttgggctt tgcccctagg gcaggggtga gcacaacctt ctctgtaaat atttcaggct 45420 ttgcaggcca tgcaaccgcc cttcgcggcc cgtatggtgt gaaagcagct cagccagggt 45480 gtaagggagt gggcgtggcc tgtgcctgtg acactggacg ctgctgcctt ggccttgggc 45540 cctagtgtgc tgcctcttgg cctagattag ctcttatcag actccctatg ggaaggaccg 45600 gtctgtttca tttccagttt gtcacaaatc gatatggggt cccactgcac agacgcaggg 45660 gctcagccag gcccagtccg gcagggtcag acagagttgg ttgtgccctt ggatgccagg 45720 gtcacgccaa ccccagaggt ctgcatgctg tcatgttctg tgcccacttc gttgcagttg 45780 gcaacgttgc agacctttgg tggagtagta ctgccctggg ctaaggctcc cagaccctgg 45840 agactgcctg ggccaggctg gggcaggtgg gcgcgtgggg atcactggaa gaggctagac 45900 ttgggaggct ttgcagtgtc ctgagtgccc tggggggggt ctctccatta gcttcatggc 45960 ccccttgcag ctcagttcct ggtgcttggt gatggctctt aagaggctgt tgagggatgg 46020 tttggccctc aaaagagagg ctggtgggag ctcccatgct ggggaagatt cattcattca 46080 ttgggagctc ccatgctggg agatccatcc atccatccat ccatccatcc atccatccat 46140 ccatccatcc atccatctgg caaatactta tcaggcgtct cgggcccgtc ctcttccagg 46200 cccttgcagt gcagctgtga acagaacagg taagcatcct tgtctcaggg agctgacctc 46260 cttgtgggga atggcgagtt gggaaggaga tgaggggaag ggctgaggtt gggggagccc 46320 agatttaagt agagagtcgg ggaggagcct cactgagaag ctgcctttgg agctgaacct 46380 ggaggaaggg agagggccag gcatgtggga atctggctga ggaatgttcc aggcagcagg 46440 aacagtatgt gcaaaggtcc tgaggtggga gctctcttga ctgtagccgc catcattccg 46500 ggagagaccc gtgaatgcag ccagggtcta ggaatgtgct gaattcttcc tttgctttcc 46560 catgaatcca gggtccagga acgggctgaa ttcttccttt cctttcagtg tgcagtccca 46620 ggcattccct tgacaccttc tggagtaagg agccctatgc aggggccaga gaggggcact 46680 cctctcccgc aaaggaactt ctcccagtcc atgctcaaac atccccccgc atctagcccc 46740 tttctcctct ctgcccccag ccactcctcc ccacccttgg gacccagcca agaaggcacc 46800 agctgggatt ccctcctgga tgaatggctt tttctggtgg cctctcacct ttcccaggag 46860 ttttaagggt gtaatttatt ggtggccctg atttccagct tcagaggtgc catggtcagg 46920 gagaaccctc tgaggccagg gggcatcacc tgaatggctt tttcctgcct ccctttctga 46980 gcagctgggt cagactccct ctgcccaagt caggtttgct gctgtcctac agggacaggt 47040 tcagagcctg gggactgtcc cctcttgtcc ctcctcagaa agccagctca gcctttgcct 47100 tgcatctcag aacgtacccc ttattgctgt gtgacgtgga caagccactt accctctctg 47160 tgcctctgtt ttctcgtctt tgtgtggggc ttcttgtaat acccacctca cagggttgct 47220 gtagggatga aattaactaa tatatttaga gcgtttagct gcaggtacac aaaggcaatt 47280 tattactgtg gggtattatt gttgtttttt atgattaatg ttgtcgcgtt ggggagctct 47340 cctgcttgga gacgtggcga ggtggtttcc agcctgggcg tattccagct catgggaccc 47400 cttgggctcc acctcaggtc agtttctctg gtggggcctc cccaattctt gccttcccct 47460 agagcctcca ggtactcttg ttgggggagt ccctgggctc aaccctggtg acctgcttca 47520 agcctagtgg tgggggccag tgtggaccga gtgtctccca gggtttaggg tccagtaaca 47580 aaatgcccac agattttggg cagaaacggc acccaagatg ctcctaggag gatctcctaa 47640 attgggaaac gaaggccaaa gggttcatgc agaggcctcc ccagccccca cttcgggcct 47700 cctccaccat ggttggctgc cgtgggcact atcgggccga ggccctcttc ccagggactg 47760 gaccgtccgc cctgcttctc tgcccacttg gccttggtat gggagagctg ggtggagagg 47820 atcctcctgg cagactgtga ggcctgctgc tttcttctca cacctctgtg tgtgtggcaa 47880 ggtctttgcc tggcagctgc gtcattgtca gcccagtggc ctcctccact ccctccctcc 47940 agccccgtct tctcccttct cctcccactg agagcaccta gagtcttgtg ctagacactg 48000 tgggatgcag gaggaggctc gtgccttttc tgccttctgg aggctgctct cagccttggg 48060 ggaatccctc agagaggtga gggagatgag tgtaggaggt gcaggcctcc tttaatctgg 48120 gctgggcacc catttcaaag aggagaaact gaggctcaga gggttagaat aacagggcca 48180 aagacacacc ttctgttgga ggccttgcag cttttggtat ctacatcgga ctgtccaggg 48240 aggtcctttc cccagctttt ccagcttctg aggctgccag ggtccccatg gattccactt 48300 gctcatcctt cctggcctct gggctcccgg gctcttatgt gctgattttg ttgggtctgc 48360 aacagataca ttatcaacgc acccacctgg cattgtctct gattctcttt gcaaaaataa 48420 ctgccttgtt gaaaaagcca gacaacaaaa gagtgactag atttttatgg aaaattggga 48480 aaattaaaaa aaggtgccaa gaagagacga agtcccttgt aatcccactc tctaaagcct 48540 tacctgtcag acatcactaa ctgattgccg caaacagcct cactgagtgt tccaggcaga 48600 cagaactaat ctattggaat tggtgcgtaa gtgaagcctg tcttgttttt gtttgagagg 48660 cttgttactg tctttttttt tttttttttt ttaaacacag tttaatgttt ctcaaatctg 48720 ggtgtacttg gcaattggta tacatctaat ttgttgatat tgagttttac cccctatgat 48780 aatggataat gtgttaaaga aacaagtatt tggactcttg ttaagcagga agaccgtaca 48840 ggacaattgt gctatcagcg tcaagactgt cacgataagg gagagagacc aggctcagcg 48900 ccaaatacgg ccaagacagc tggggcctca tagcctagcc gcagggcgga gggaggggtc 48960 ggtggatgga aaattactaa gaggagcgct tgagggtggg gggttcctct agactgactt 49020 agcaggatgc ctgcagctgg gcagagcccc gcaaggccaa ggccaaggcc gaggccccgt 49080 agagagagga tgggtcagag gagcttgact caggtgtggg caaggagagt ctttgtcaaa 49140 tggacgacgg tgtgttatta aaggaggaag gtctgcctaa ggcttaccct tctggctgtg 49200 atacgagcgg ggagttcctc ttttacaggg cggccttggg gtcaggggtc gctttgttct 49260 gaaacctggt ctttgggcct cgctggctgt cgggtgtttg tcgccatcac ttgccaccat 49320 ccatccttct cctggcgagt gaggcccgag cctcgttccc tcgcgtgggc atcacttacc 49380 caccctgcca agagctgggc atctaggttg ggccttttcc cagttgttgc tgcaaatgca 49440 tttctgtttt tacaaataat gctgccccgt atgcaccttc agtcctgtct tcccaggcct 49500 gcatttccaa gcttcagctc ctcaggctgg agggacccac agcctggcag gggtaggatg 49560 gggtgggagg gtagaaaagc gaagacagct tcctctactc tggcccccca gtcaacgcca 49620 gcatggccgg cagacagagg ccatggttag gatggttcca ggcctgtatt agcctgtggc 49680 ctcagacagc cccatcagac ctcccaggct tggcggtctc atttggaagg tgggcgtgat 49740 cgtgggtccc tgggatgctg tgtgggaagg atgcagccca gggccgttca gctgtgttct 49800 ttctcctcct tggtgttcgg ccccaagggt agcctctggc cagacggtcc ctgaggttcc 49860 ctgcaggact tgggcttatc tgcctagggc aggagcgagc ctgagcaggg agtccacggc 49920 cttgcccact gtgccctgcc gtgccccgcc atgcccgtgc ccgcccacgc tcaccactcc 49980 tctgtcccct cctgcaggac gtcgggctcc tggagtacca gcaccactcc cgcgactatg 50040 cctcccacct gtcgcccggc tccatcatcc agccccagcg gcggaggccc tccctgctgt 50100 ctgagttcca gcccgggaat gaacggtgag gagagagttg ctgcctccct gtccagggcg 50160 tgagagctcc ttctcagatg gagaagcaga ggcccgtggc agagcaggag cacacagggt 50220 cctgtgaaat gaggggatgt cgggccgtgt gttcaccctt gacctggcgt gggcgtgact 50280 cggggtgagg atgggacgag cagggaagag ccacgtggcc ctcagacttc cagcgtggaa 50340 cttcagtggc ctctgtgggt ttaggcagca gtggggacct ccaagctggg ctgcagcagg 50400 gctgggcttc tgtgggaaga tttgagtcca cacctggtgc ccctggggcc cctgccctct 50460 cctcccattc ttccttcttc tccagctggc agaggacacc ctctggtgtg tgcctgtgct 50520 gggccagcct tactttcctt gatccaggtg ggaagggaat gaacaggtta ggtggtaggg 50580 tgagagggag gtggggtggg gagctggagg gactacagca aggggagggc cagggctggg 50640 tcagagccag ctctccatgc attcacttgg gatcggtagg ccacgttctt tctcccatct 50700 tctctaggag cttctgctgg agacggctga ggtgtgggga attgtgccta tttctcagat 50760 ggggcagctg aggctgcgag gttgagggat gggctcttgt ttactcagcc aggactagaa 50820 gtcgaggcac caggccccag cccttcatgg taccacggag gtgtcccagg gccccagatc 50880 aggcggggct ggtgaactca ggtgggcgca ggcgtctgga ggaggggagg ccgaggcagc 50940 gtgccttctg tacctggatt ggtttcctgg gcctgccgtc gcaacgtgcc acaaactggg 51000 cggcttcaag ccacagaagt gcattcctgt gatctgaagt cagggcgtcc gcagggccgc 51060 gccccctcag aaggctcaag gggaggatgc ttttctgtct cctccagctt ctgggggcta 51120 caggcgttcc tcagctgtgg ctgcatcggt ccaatctctg cctctgcctc tgcctctgtc 51180 tcacgtggcc atttccttgt ctgtctctgt gttctcttgt tgtgttacaa ggatcccagt 51240 gatcctaatc caggatggcc tcatcttagc ttaattccat ctgcaatgac cctaggtcca 51300 aagaaggtct tattttgagg ttccagtggc tgtgcatttt gggaggatgt tatatttgga 51360 ggttccagtg gccgtggatt ttgggaggac attatttgag ccactgcagt gccactatca 51420 tgtttaagag aaaacaccat gcgcttcctg ccaagcccca tgtaatggtg aagccctggg 51480 ttctgggcct tgaagagggg gatgtcttgg ggcccagctt tggagggaca aggacttgag 51540 ggccctccag ggaggtgagc acagaggggt ggctgccccg ctccccgggg gggccagcaa 51600 cacggcccca gcccgtgctg cagtgggcag cattcagtca gtctacaggc actgattgaa 51660 cacctactgt gcgccagtac ctggggacag ccatgaacaa gacaggtgaa ccaccctgcg 51720 ttcattcatg ggtgggggag gtggccagga aacacctgtt gtcaccaagc gcgtgggagg 51780 gcagtggaga gagagcagac aggcgggtgt agtgtggtct ggcctgggac aaggaggcgc 51840 catctgcacc atgacaggaa ggggaggagc tcacatggag ggcctgaggt ctcagtgctc 51900 caggcagagc ccagcaggtg caaaggccct ggggcaggag tgcagtggcg ggacagcgag 51960 ggccaggcca ggcagggctt gtgcaggagg ggaacagctg tggattccct gcttagcctc 52020 tgggaaaagc atttcagcaa ggcccatatt caggctcttt ctggtgggtg atggttggag 52080 cctcagaggt ggaggccagg agtcccagct ccgtggggtg tgcttagtta ggcaaggcca 52140 tgccctctct aggcacactg cggaggaggg ttcaggagag ccagtcgctg gggaaactgg 52200 gcagctccag tctctgcacc aggctgctag gctgagttga gaaggtggtt aggccaggtt 52260 cagcagcaag agttctgcga tcggccagcg atgtctgccc tgcgtgggtg agagggaaat 52320 ggcatcacgg gtgctgttat ctgtgttagg ctcacagcgt ttcccggatg gactgtgcct 52380 gtgaaccacc caatgatctt gttaaaatgc cgagtctgac tcagtaggcc tcagatggta 52440 ctggagattc tgcattgtag ccagccccag gtggggacgg tggggtggtc cgtagcaagg 52500 gaggggcagt cactctgggg tgttccagtg ccaccgtagc acactccctc cctgtaaatg 52560 tcctcggtga atgtggacct gaaggaaggc agcgctgcat tggagtcctg ccctgctgtg 52620 ggaccgtggg aggtgggctc ctgtgagcac cttcctggca ggatcataca gagcacggcg 52680 cgcagtagat gctcggcgca gagggtggtc ggggcctcgg gagttctcag agccacaatc 52740 tcctatgtga cgttggatgc ctcacctcct gcaggtccca ggagctccac ctgcggccag 52800 agtcccactc atacctgccc gagctgggga agtcagagat ggagttcatt gaaagcaagc 52860 gccctcggct agagctgctg cctgaccccc tgctgcgacc gtcacccctg ctggccacgg 52920 gccagcctgc gggatctgaa gacctcacca aggtaagcct gggcccccag ctgggagctc 52980 ctctcccgct tgaggttctg ctgctggttg ggctgggtgg gaggtggtgg gtaggggtgc 53040 agggaggggg cagctcgggc aaaggcttgg aggtgggcca agcaccgggt gcacagagct 53100 gggtggcagg aagagggcag gcgctgggtc tctggaggtg ccagagtgtg ggaagaagtg 53160 gggaaggtgt tccaggtggg cagagcagca agtgcaaagg ccctggggca ggaataggct 53220 tgtggtcacg gggtagctgg cgtgagggag gggagagctg ggatgggagg gcctggggtg 53280 ccgtggagca gagagctgcc attcgatggg ggtcaggacc gtcctgtggt cggtgggcag 53340 ctttcagcac attctgagag cttcctcgag ggtgggttgt ttggttccat gcttgcttgg 53400 aacagggggc tcagtgaccc ctgcctcgag ccctgcacag caggcagccc cctgggcctt 53460 gaaccccggc ccgcgaggtg gacagctcag ggctctgcca ggcacctgag gcttctggat 53520 tcttaagggt cagggagggg agactccaga gtcccgcaaa gtgagatgag acagagttgg 53580 ctcagcacta aaggggcggt gcttggttag gacatggcct ggacccctag aatgacaaag 53640 ccgccttcta ctgcccagtc tggctgctcc ttgggccacc gtgtggcact gggctagcgt 53700 gggttgagtc tgcagccacc caggcctgag ggaccacgga tgcactttgg gcaggggagc 53760 cagacaactt caggctcgtc tgcatctcca tggggggctg cctggcattg caggtgggcc 53820 caggcctcac ctgggcacac tcacttatcc cagggccctc cgtccatctg ccctcaggtg 53880 acccaggtgc gatttccacc acccccacct ccacagctgt gctgcctttg tgcctctctg 53940 atccccattt cttcctcact gatctgggac cttgtgggca gggtgtcacc tggtcatgtg 54000 ggtagagggc tcggctgtgg gccccatgcg tgggaactat ttggcacccg tgagccggca 54060 tgggtggtgg tctggctgcg gggccaggcc acctgggcca gactcggcct tctctcgggg 54120 agagaggata cctgcgtgga acctgggata tccctggggt gggcttgggc tggcaggagg 54180 tgggggtgcc gtcctggggc tgggatggct gggcttcccc tcctgctctg agtggctgtg 54240 gccccgacac ctgcacacct gccagatacc cacagggctg cctctggggc caggggaggg 54300 aggggctggg gtgtctgtgt ggtcgttggc tggcttggcc tccctgccac tggggcagtc 54360 cccgcctcac caagttgtca caggaaagtg gaggtcagtt aatgaactcc tagccaacag 54420 accacatgcg cctgagagcc cactcaggaa cctcccccgg cggatgcagc tgtgttcttg 54480 ttggcactca gggactccac cctggccacc tccctgctct cctgcgtact tccagtccat 54540 cagcaaatcc tgacacctct gccctaaaat atctcaattc cagccttctg cccacacctg 54600 aggcaacccc cggcctgagc tcgtcattgc tctccagtaa ctttgcagta gcctcctcct 54660 gggtctccct gctcctgcct ccctctactc ccttcagttt atcttccaag cagcagccag 54720 agggctctta taaaggcaga cgactgcatc cccctgtgtg ttcccccctg tgctccaaac 54780 catccatggc tcctgtctca agcaggaaaa agccaaaatc cttgccatgg gctgcaggtc 54840 cggcgtgatc cagccccgtc acctccctga cctcatctcc ctgcagcagc cctctcaacc 54900 gctcacgtac agcctcccag gccaccctgg agttcctcaa acacgccagg cacattccca 54960 cctggggacc tttgcaccgg ctgtgccctc cgcaggagcg ccctccccca ggcacattcc 55020 tctttcctcg ctccttccag ccctggctgc cctccagggc ctgcatggca ggggagacct 55080 gtggctagcc ctgtggggac tctcgaggcc actcatggct gaggctgcag ccccaccacg 55140 tcctcctggg gtgtgagatt cagccacagg ggccctgccg gccttgaagg gggtctctgt 55200 ggcctggggc ttggccgcct gcacttgggt ctgggcttgg gactggtgtc gatgccagtt 55260 cctctcgggc actgcccctc gggtacccca gccagcatcc ctgccccgac gcccaaccct 55320 tccagcacat ccttcctgcc cttcctcccc ttccttctct ccttctacac cttcctccct 55380 ccttcttcct ccctctcttt ctttccaccc aaacagcccc cctgtcctgc tcactcccct 55440 tcaccccctg cttcctcagc tcctgccaac tctccctgct catcccctgg ggcaacctcc 55500 ctaccacaga gccactccca gccaccaccc agcgccaccc agcccatctg cctgcggcca 55560 tctgtccttg ccttcattac ctgcccctcc ccctcacctc ccagccgccc ctcacccatg 55620 ggttctgcct gccatcatct cccaccagtg gccttgcccc tcccccatcc actcacctcc 55680 cccattccct tgctccccca ccccctaccc ccatccgctc cccctccttc ccccactcgc 55740 ctggagtcca gggtcctgtg agcccagtca gcccttgcag gaactcacaa ctcacagccg 55800 gacaagggcg cctgggggtg cttggcccgt ggccatttct tggctggaga acgacacctc 55860 ccacgtgtgt gtccagcctg gggcctgcca cgcctccagt gccctccaca gccctttgat 55920 ttcactcctc tttgaaacag aaagtggaac ctagacggtg gcggtggtga ggatgtgcac 55980 agattaagca cctgtggttt gctgctgtgg gagtttgctg tggtttcagt aaagctcagg 56040 acataccagg ctggaggctt gttctctctc cagcttccac agaggatgcc gatggcaggg 56100 ctggtggggg aatcgcaggc agtgtcccca gaggcttcag tcccccaggg tcactcagcc 56160 acccagctgt gtctgactgc ccaggccagg gtggggctgt ggccaggtgg catcctaatc 56220 cttgttgtag cctggtgccc ggccagctgt gacacgggcc cctccctgca cagccctggg 56280 gcaccctaag ctccttagca gcctcagggc aaaggccatc ctcctcctgc agcgggagta 56340 ggggtgggcg gtggggactg ggagacagcc ccggggaggg aagtggccac tcaggcctac 56400 agggtcccct tttctgccca gtgcggccgg attggattga atggttgacc cctagggtga 56460 ggcacctcct ttatcaggag gctggcacgc aggaggcatt cacgcagtgg taagaatgct 56520 gcagtgatgg cgggtgccat taagtgagcg ccgactgcct gccacgtgcc aagtcatgcc 56580 cagccagtgt cattccctga tctcttccca gcccaaggag gctgggtctg tgaccccctt 56640 ttgtagacgg ccccaggctg agcgagctgg acgtggggga acgggattca ggcccaggca 56700 gctgggagtg caccccatgc ctgcctccag gttgacctgc tgctgtgggt ctcccctctg 56760 gtctccctgg tggggtgccc tcctccctct gcctggcatc ccccattagc actggaatct 56820 gctttctcct cttttgtttt gttttgttgt tacagaaggc aggagagaat tttagctcag 56880 cctcctggga gagatgtttc catttgaaca actcccctga agtggggcct ggatggatag 56940 caggccaggg tgtgtgtgtg catgcgcgcg cgcgtgcgtg tgtgtgcgcg tttgtgtgtg 57000 ggtgcgggtg tgtgcgtgcg tgtgcgcgca tgtgcgtgtg tatgcgcgca tgtgcctgtg 57060 tgtgtccctg cgtgtgtgtg tgtatgcgtg tgtgcacaca tctgcctgtg tgcgtgcatg 57120 tacctgtgtg tgcgtgcgtg tgtccatgcg tgtttgtgtg tgtgcgtgag tgtgcatgtg 57180 ttgcacgtgt gtatgtgtgt ttgtgtgcgc acgtgtgtgc atgtgtccgt gcatgtgcgt 57240 gagtgtgcat gtgtgtatat gcatgtgtgc gtgtgtttgt gtgtgcgtgt gtgtgcatgt 57300 gcacgtgtgt gtgcatgtgt ttgtgcgcag gcagctcagg gcccagcctt ggagggtgac 57360 caacccctga gtgggcagtt gtcccccagg tgcgcgtttt gtctctgcgc agagagcagg 57420 cccgaggggt gagttgctgc ctgcccgcct ctccagcacg tccgtgcgct ctggcctgtg 57480 ggttctggag ggtctccatc ccttaccgtt gctctgtggg ttctggaggg tctccgtccc 57540 ttaccgttgc tctgtggttc tttctgcctg cctggctttc cctcttcttg tcaggaatgc 57600 ctctgcctgt ggtgcgccct ctgggatctc tcttagtctc tgtgtctgtc tctgtctgtg 57660 tctctgcctc tccatctctt tctctttgtg tccctctatc tctatctctt tctctttgtg 57720 tgtgtctgtc accacgtctc tgtctttctg tctctgtttc tgtcttcatc tatgtccatt 57780 tctgtttctc gatctgtctg tctgtcttcg tctctgtgtc tgtctctctc tcctctctgc 57840 ttggaccaca aggtggaggt gtgatgagct tggtgctggg gcctgaccag cctggccgca 57900 gtaattgctc caggccgtga agagatttgg aaagtctgag caagggaaga tgcctgggag 57960 agcgagttga gaggttttct gcatctgctg tgtggaattc agctgggcgc ctgaggcagg 58020 aatttgatgg gatttttctg tgtgtgcccc ctctgcccca ccgtgttcct gttttctgat 58080 gcttctctgc tcttcagcct ccggagtttt gtggcatcag agacttcctt gggaattcac 58140 cgaactttgt tttggggact ttagaattgt cacaaatagc actatctctg aaaatcccta 58200 agggggacag acagccccta tcaaatataa acatgaattc tggctcacat aactgaagtc 58260 cagcattggt tagcttcagg taacagcttg atctaggtga cacgatgtcc tcaggaccct 58320 gtcccttttc atcccttggc tctgccatct ttcacagggt cttggtgtgt tagcaggaag 58380 gaagccggtg actccaggcc ttcctccagg ttcaaggcca gcaaaaagag agaactcttc 58440 ctcctcctct ccgcatttct agccccaaac tgcttttcct cctcaccatg agtgggccca 58500 tgcctgtcct agaacctgtc attgtggccg gagtaggggg tgtattggga gtgcgtgaag 58560 ctgggccctg ctttttcctg gagctggcac aggggagccc aggggctttt ctgcctctct 58620 gtcttcagtt ttgcataata aacttttctc tttcacgcta gcttgaagtt tacaccaggg 58680 gcatctgatg agtaagaggt acccactgcc ccctggcaac ttgtgcgggg tgtattagtt 58740 tgttgttttg ttccctgcag ctttgggtga gtgggaaggt ggacagtcat caggagtgca 58800 cctgcaggcc tgaccgccag gctccctcag cccccgtcct gggaaaccca gcaccagggg 58860 aagcgctctt ggcaatccgg gtttgcctct tctttttcag ttgagggtcg gttcacaaaa 58920 aagtaaccac attaaagtga agagctcgtt ggcttgtagg acatttacaa tgttgtgcag 58980 ctgtcacctg tctagttcta gatcattctc atcaccccaa aaggagaccc ccatactcat 59040 taatcagtca ctccctgtgt tagtctgttc ttacaccgct aataaagaca tacccgagac 59100 agggtaattt ataatagaaa aaggtttagt tgactcacag ttctgcatgg ctggagaggc 59160 ctcaggaaac tcacagtcgt ggtggaaggg gaagcaaaca cgtccttctt cacatggcag 59220 cagcaagaag tgctgagcaa aagtggggaa agccccttat aaaccatcag atctcatgag 59280 aactcactca ccatcatgag aacaggacgg gggaaaccgc caccatgatt caatgacctc 59340 cacttggccc ctcccatgac atgtgggaat tatgggaact acaattcaag atgagatttg 59400 ggtggggaca cggccaaacc atgtcacccc ccacttcccc ctcctccttt ttcctggcaa 59460 ccacgaatca ctgtccatct ctctggattt gcctattctg gacatttctt gtaagtggaa 59520 ttgtacactc tgcagccttt tatgtctgtc cacttccact cagcatcata ttctcggggt 59580 tcatccacag tgtagcctgg gtcagtgctt cattcctttt tttttttttt ttttaataaa 59640 gatggggtct tgctatgttg cccaggcggt cttgaactcc tgggctcaag caatcctcct 59700 gcctcggcct ccatgtccag cccttcacat tgcttgtatg gatatgccat gttttattta 59760 tctgttcatc aggtgatgga cttacttgtg caattttgct gcgaataaaa gctaaacccg 59820 aacttaaaga agaacccatt aaagacaacg gcttttatcc atggagagtt taaaggaagt 59880 aagttttcag caacttttcc aagtgttgct agtggttgcc agccgctgct tttactcctg 59940 gtgctgcctg ttagccctgg ggatggaaat cttctttttg ttaatgttgc tttggagaat 60000 tattcccagg ttggacgagc agtttgctct cagagtttta gggtggcctg gcccccatag 60060 cccttccttc cacatccttg tccttgctct gttatctctc ttcttggtcc aggtggaaga 60120 gcagagatag gatagcggag atgtttcttg ccaccagtag tgcgaccggg ctctgggtgc 60180 catgtttgct gccacctttt gtcttaagaa cctcaagaaa tgacatgggc tgtagggaga 60240 gaccagccaa gcacccaagg tggaccgcag tgagggcctg ggcggtggcg tggggatgtc 60300 tcacgtcagt tggcacagaa ggggtgttgg gcactctggg tagcggagcc agcctgtgca 60360 aaggcccggg ggtgccagac gcatgagctg tccatggttt gctgtgggtg gggtcagatg 60420 cccatggccc cctgcctgcc ttcctgttgg ggagcagtga gggccccaca cccactggta 60480 cgtgcataca cactcctgag gctttttcta gggagttttt cttccacaca cacttttgcc 60540 ttgagtttct ggaggtcctg cactctgggt ccctggaagg ggtgctgctt tggcgcttat 60600 gctcagccct atggttctgt ggggtgaacg gatgtgtggc tgggacccca cgtggagtcc 60660 ccacatggct cagccccacg gttctgtggg gtgaacagat gtgtggccat ttctgacgtg 60720 ggagcccctg cagcctcccc cttcaagcac cttccaaggt aggatgctga gtggccttgg 60780 gcatgtcgtc aaacagaaat cccacttccc acggtggtta tgacggttac gtggattaag 60840 atttgtgaat tgcttagagc aggaggccag caaactccag caagctccaa atctggccct 60900 cagtgtgttt ttgtaaataa agttttattg gcacacagcc atgcccattt gttccccgtt 60960 gcctgtggct gcttttgcaa tacaatggca ggggtgagta gatgagacag agaccttgtg 61020 gccctcaaag cttgagctat ttttaccatc tggcccttta taggaaagtg ccggcctctg 61080 gcatccagcc ccagtggcct ccaggctctg tttctgcctc tgcgtaatgg agatggagca 61140 gcagtcccct cggagggctg ttgtgggatc cacttcatgg ggtgtgcaga ggacttcatg 61200 gggtgtgcag aggactggga taggctgagc tgtgagcagc cccaggtgtg atttctaggt 61260 gtccctgggg gaggtggcct gaggagcatg gaggactgca ttggggcgat tgagggatat 61320 gagccctttt ctctgtttcc ctcgaggagt ccgtgtgtgt ggagggagca ccgggttgtc 61380 caggcccctg ctgtccttgc ccccacatct cacatggtaa cagaggccag aggcaaacct 61440 aatgtgactc caagactctt ggcccctgtg ggtcttgctg gggctctgtg gggtgagggg 61500 aggacagagg ccctgaggat ggcaggagtg gacagaagat gatgcagcct ctgtgaatcc 61560 tgaggttggt ggggcactcg gtggcccccg ggctgcagtt gtccggagaa taatgcaccc 61620 tgtgtcctct gggtgcagct gctgcggggg cggggaggtg gtggcctggc gctgctctgg 61680 gccttgtctg ccagcagctg ccggcttggc cccaaggatg gcacagggcg ggggctgggt 61740 tctggagccc agctagggga ggaccatccc agccaacatt tattgaggct tacggtatgc 61800 caggctcaga gccattaact cattcaagac tcacaaggac cggggaggtg ccagctgttc 61860 tccccattgg gcagatgagg aactgaggca ggaagcagtt gaatgacctg ctggaggtca 61920 cggaactgga gagtggcaga gggggctggg atttgaaccc agggctgcac aggtgaggcc 61980 tgggttgttt tttctaacct ccttatcctg agagtgtttc cagcacagcc tgggtgcacc 62040 agactttagc tggtgggatg aaggcgtcca tggataactg aatgcaggct tcctttgttg 62100 ttaagcacat tttcaaaaac agctgtatta cacaaagagt gactctcagt gaaagaagat 62160 cagaaaaaat aacgggcaaa taaaaagaag aaagtaaaaa taccctcttc tgccctgctg 62220 ccgagataac tccttttagc ttaactgtag cccgttctga tggcttttcc gtgtgtttgg 62280 gaacatatgt tttctgcaaa gccacgtgtg tgttggctgc atggttctgg aacttgcgtg 62340 tttggactga gcttcatgga tgaatgttta cagagggtat gcagaggcca ggccttggga 62400 gaatggaggc tgtgggtctt ggttccttgg gctggtgggg aacacacaga tggggtaagt 62460 ggaagaagag aggtgtgtta cgcgaacagg gagttggaag acttcacaac ttgaggagag 62520 gctgggaaac cattcatgta gcaagagcat ttgaaccgca tcttgaaggc tgtaagggac 62580 tctgaatttt ggagaatggg tgatggctgg gatgggaatg ggatccttga acaggtgagg 62640 actgtcctga cagatgtcca ggactctggg cctggagtca gggatggaaa cccggggtgt 62700 attggggagg gggtgtgtat tagtccgttt tcatgctgct gataaagaca tacccaagac 62760 tggtcaattt aaaaaagaaa gaggtttaat tgtactcaca gttccatgtg gctgtggagg 62820 gctcacaatc atggcggagg gcaaagagga gcaagtcaca tcttacatgg atggcagcag 62880 gcaaaaagtt ggcaactaca ttagtcaggg ttctctagag ggacagaact aatagaaaaa 62940 atatatatat atattacata aaggggagtt tattaaggag tattaactca cacgatcaca 63000 aggtcccaca acaggccatc tgcaggctga gaagcaagga agccagtctg agtcccaaag 63060 cttgaagaac ttggagtgtg atgttcgagg gcaggaagca tccagcacgg gagaaagatg 63120 taggctggga ggctaggcca gtctcgcctt tgcacatttt tctgtctgct ttatattcgc 63180 tggcagctga ttagatggtg cctacacaga ttaagggtgg gtctgccttc tccagcccac 63240 tgactcaaat gttaatctcc tttggcaaca ccctcacaga cataccgagg atcaatactt 63300 tgcctccttc aatccaatca ggttgacagt attaaccatc acagggttgt acagactggg 63360 gggtgtcccc tgtgctgacc ccatgcccgt tttttttctg ccacaggacc gtagcctgac 63420 gggcaagctg gaaccggtgt ctccccccag ccccccgcac actgaccctg agctggagct 63480 ggtgccgcca cggctgtcca aggaggagct gatccagaac atggaccgcg tggaccgaga 63540 gatcaccatg gtagagcagc agatctctaa gctgaagaag aagcaggtgt gaatgggcag 63600 ggggaggggg agtgtttgtt ctgagtctcc attctagcag cagtgacagc ggtgtcacag 63660 acatgtgcca agcccttccc aagttcctgg gtgctcactg gtttttatgc cctttacgtt 63720 tattggacag gagcacatcc acagaacttt ctgccatgat ggaaacactg tgtatctgca 63780 ggatagccat gttccactgt tgagcatttg aaatgtgcct actgcgactg aggaactgat 63840 ttttaatttt tatttaatat acgtattaaa tgtgcctttg aatagccaca caggctgccg 63900 cattagacag cacaagaatg gagggtgaaa attcaggatt tctagccagt ctgtccaggt 63960 tcagatcctg tttcttccag taccaggcaa cgtggggtgg gcagtccctt ctctgtgctt 64020 cactttcctt atctgtaatg tggggaaaca gcccctggct ctggaatctg aatggactgg 64080 cctcctaact gctctttact agctgtgtgg ccctggaacc ttcatctctt ggagccttgg 64140 tttccttgcc tgtaaaatgg acaacttgta gaggagggag caagatcccg agattaaaaa 64200 taaatcctca ttgtcactgt tgaaaccaca caaagacaag cggagaaaaa gctgatataa 64260 atatttataa cattcatttt ataactttgt tttaaatatg agttaatata caattctttg 64320 ataatctgcc ttttcccagc tcttcatggt ttgctccctg gtatcattca ggtctctgct 64380 cagatgtccc tgacaccaag aggccactgt cagccttgta caggaacaca cacccccaac 64440 cctcctctat cccgggttca gccaatccag ccaattctag ctgctgctgg tttttgtaaa 64500 taaagtttta ttggcacagc cacgaccact tatttgtgta tctgtataca catgtgtgtt 64560 tatatgactg cttttctgcc acagtggcag agttaagtca tcacaacaga gacctgtgtg 64620 gcctgcaaag tcaaaaatat ttgctgttta ggcctttaaa gaaaagcttt gggctgggca 64680 tggtggctga tgcctgtaat cccagcactt tgggaggctg aggctggagg atcacttgag 64740 cccgggagtt tgagaccagc gtgggcaaca tagcgagacc ctgtctctac aaataattta 64800 aaacattagc caggtgtgga ggcacatgcc tgtggtcaca gctactcagg aggctgaggc 64860 aggagtgcct gagcccagga ggtttaggct gcatgagcca tgattgccac tgcactcttg 64920 cctgggcaac agagtgagac tctatctcaa caaaaagaaa ttttgctgat cactgatctg 64980 tctcatcacc ctgctggtga catcattatt tgaattaata tagacccagc tttgttatac 65040 agtggtcctc tccttgtctc cctgttaact gctgtgttct gagcagcatg gggtacatag 65100 taggtgctca ttaaaaatgg ttgattgagt cattgtgaca ctgtctgggc cccagggagc 65160 gtctagacta atgggagaaa caggctcata tctagtgccc tccagacaag gaagtagggg 65220 ctccaaggag gatcaagggc tcattttagc cactgtaggc aggtgggtga aggctggtga 65280 gagtaggctt ccaggaagag gtgccctggt agctgggttt tgaaggacgc tccaggggga 65340 gagcattgat ttcaagtgtc catcgtggct gtcacgtggt tgggggaacc aggatttgag 65400 gatagtccag cagtgagacc cggtcctgga gactctgcca actgtcctag gcttcagtgg 65460 gcagtgggta ggtctcatgt tggtggcaca ggcatcccga gaggggccgg gccccagcgg 65520 cgtgggcagg cattgccagg gccagcctgg taccgcaccg ttaggcttcc aggcctggcc 65580 ttggggtggg gctgaagctg cgggtcactg gcacacattg gtgactgcag ctggaagcca 65640 ggtggctcaa ggcagccctc aatggttagg tttttgtttg tttgtttttt cccctctaaa 65700 ttccactttg gcatttttta aaagtgaaat tctcaagcat aattatttta aagtgcacaa 65760 ttcagtggca tttcgtacat ttgcagtgtt gtgcagctgt cacctctctc tggttcccag 65820 ccatttcaac aacccacagg gaagcctcat aggagctaaa gcagccactc cccgttcccc 65880 tactctctgt ctctatggac tgacctgttc tagacatttc ctatataggg catcacacag 65940 tatgcgtcct ttctggcttc ttccacatag tgtcatggtt ttggagttta tcatgttgtc 66000 tcttgtctcc atccttcatt cctttttatg gctgaaacat attccgttgt atggagatgc 66060 ctccttttgt ttatttcatc atctgtggcc atttgggctg tggctgttgt gaatagtgct 66120 gctgttgaac atttgtgttg aagtttttgt tgggacacct gttttcagtt ctcatgggta 66180 tatacctagg agcagaattg ctgggtcgtg tcgtacagta actctaggtt taatttgctg 66240 atgactttcc aggctgtttt ccacatcagc tgccccattt tacattctta ccagcaatgc 66300 atgaagattc ctggtttcct ggttttccac atcctcaccg accgcccccc agcttttttt 66360 tttttttttt ctgagatgga ttctcactct gttgcccagg ctggagtgca gtggtgccat 66420 cttggctcac tggagcctct acctcctggg ctcaagcgat ccttctacct cagccttctg 66480 agtagctggg agtacaggtg tgcatcacca caccgagcta atttttgtgt tttttgtaga 66540 gatggggttt caccatgttg cccaagctgg tctcaaactg ctggtcttga gtgatctgcc 66600 caccttggcc tctcaaagtg ctgggatttc aggtgtgagc cactgtccct agccacacca 66660 accctttttt atcttccttt aaaaaatgtt tttgattcca gccatcctag tggttgtaca 66720 gcggtatctc attgtggttt tgatttgcat tagagagccc tttatagcgt gtcactgctg 66780 tgcagcagtt ttttcagcat tatctccttg atcttccaaa caaccttatg aggtaggcat 66840 atacccacag gttctgctga agtagacact gaggtcaggg aggtgaaggg ccctggctga 66900 ggctgcagag ctggtgagcg gggggctcag gcttgaatcc aggcccagca gagctagtca 66960 ccctcttagc tgggtctctg taggtgtccc aggtagtatt ttctctagta cctgaggaag 67020 ggccaccttc cctggctgga gggagcctcc ctcctgccca ccctttcggg gctgtgggct 67080 tcttcccctt cttggctttg tttgttccgt gctttggggg agcattttga tgcccttctt 67140 gaagcgacca ccaggggtcg ctgtgggact gaggcagttc tgctcaaacc gccagcgatg 67200 gagtctgtaa aagccagcat cctggatttt ctggcttttc ctgtgttcac ttcttcttgg 67260 gcacctttct gggttcatac tgatctgctc tgtggtaatg tgcaggctgt gcgagcgtca 67320 taagtggagc agaaccatgt tctgatctca cttgtgatgc cctgtcacat tgcagaatgg 67380 ggcattggcc ttccatctga ccttgggcca gtgccctaaa ccctctggtc ttcagcctcc 67440 ctcttgctat gaagcagacg gcagcatgat gggatgctct ttccaacggt gttaggagga 67500 gggggttcat acatggacag atgaggatga ggatgatggg ggtgatgagg atgagggtga 67560 tgggggtgat gaggatgagg gtgatggggg tgatgaggat gatgggggtg atgaggatga 67620 ggatgatggg gtgatgagga tgaggatgat gggggtgatg agtatgagga tgatggggtg 67680 atgaggatga ggatgatggg gtgatgagga tgaggatgat gggggtgatg aggatgagga 67740 tgatgagggt gatgaggatg atgagggtga tgggcgtgat gaggatgagg gtgatgagga 67800 tgatgggggt gatgaggatg aggatgaggg ggctgatgag gatgaggggg gtgatgagga 67860 tgaggggggt gataaggatg agggtgatga ggatgagggt gaagagggtg atgaggatga 67920 gggtgaagag ggtgatgagg atgagggtga tgggggtgat gaggatgagg atgatggggg 67980 tgatgaggat gagggtgatg gggtgatgag gatgaggatg atgggggtga tgaggatgag 68040 ggtgatgggg tgatgaggat gaggatgatg ggggtgatga ggatgaggat gatggggtga 68100 tgaggatgag gatgatgggg gtgatgagga tgaggatgat gggggtgatg aggatgaggg 68160 tgatgggggt gatgagaatg aggatgatgg ggtgatgagg atgaggatga tgggggtgat 68220 gaggatgagg gtgatgagga tgagggtgat gggggtgatg aggatgagga taatgggggt 68280 gatggggatg aagatgaggg gggtgatgag gatgacagtg atgaggatga ggacgagcag 68340 ggtgatgagg atgcaggtga tggggtgatg aggaagagga tgatgggggt gatgaggatg 68400 agggtgatgg gggtcatgag gatgacgagg atgatgaggg tgatgaggat gaagatgatg 68460 ggggtgatga ggatgaggat catgggggta gtgaggatga ggatgatggg ggtagtgagg 68520 atgaggatga tgggggtgat gaggatgagg atgatggggg tgatgaggat gaggatgatg 68580 gggttgatga ggagcacttg tgtgtcaggt gctgcgtgct ttgcatgcat catgagctca 68640 tttcaccttc acaacggctc tctagagtag taactctttt atccccattt tccagaagag 68700 gaaggtaagg cttagagagg tccaggagct tctcaaggct acgcagtaag taggagtggg 68760 agttgggctc cagtctcacc agtgcagctg tggagtctgc acagcctctc ctagcactga 68820 tgctgcctgt aggaaccgta atgggtaata atgccggctc ggagcaggcc tgactgtgcc 68880 tgcctgtgta actcattcag ttctcaccac agtcagaatg gcggcacggc aatcagcccc 68940 gtttactgat ggggcaactg agggctagca gggtgaggct gcttggctgt gcttccctgg 69000 ctggcaagtc acgaaggcag gatttgaacc tggctttgga gcttggaggc tgcagctggc 69060 cctggagctg gggcctctcc cgggtgcgga gtccctgggg tgactcacag gaaatgtgta 69120 gcagcctgac ttcctgtgcg cggccgtggc ccgggctgca agggggcctc cccgcgccct 69180 gggggctgca gccctccttc cgcccgctgg ggtgctcatc cctcacgttc tgcctctccc 69240 cacagcaaca gctggaggag gaggctgcca agccgcccga gcctgagaag cccgtgtcac 69300 cgccgcccat cgagtcgaag caccgcagcc tggtgcagat catctacgac gagaaccggg 69360 tatgtgtccc cgccctggcc tgctgccccc cggtgctggc catgaggcgc ttcacagggg 69420 gcaccatgaa tcaggcctca gtgtttccat ctatgtgggg aggggacctc gccaccctct 69480 cccccagaga cgcagggttt atgagtgggt gggggaaggt gaccggtgga aagccatcct 69540 ggtgtggcct ctgggctgtt ctgctcagac actcagatgg gtgtggactg tggctggtca 69600 gcaggatgca acacaaaaca gaggttttgg gctccaggag agcaccaggg tccagctcat 69660 ggccaagggt aaggggctgc cactttaggt gctggtgcag aagaaatccc tttaaggcaa 69720 aagataatga cattatgacc gcagcagtga ggtttcatgg agcagcccct cctgtcagtc 69780 ctggaagggc aggtacaggt gtcatttcca ttttcctaag gcccagagag gttaagtgac 69840 ttgtccagag tcacacagct aggaagcatt ggacctggat ttgaacctgt gggctgtcag 69900 accacagggc ctgagttctc agcactggct tccactgaca ctgggccctg gaaggggcct 69960 ttgagatgat tgaaacacag agtctggagc aggctgtgga ggcccatgga gatcccactg 70020 ggggcagcta tagtgggtct ggtcttgctg gaggggcttg ggatgctcag agcagtgtct 70080 ccaggggctg gaccctaagg gtctgtgcac ccccaaggtg gaaccttgtg tctggtgagg 70140 tggtaagctc cccatcttcc cagtcaagcc actaccagct gggctttaat gatttacagt 70200 gtactttttc taaatgtact caggatctgt ggatgttgat cccctccctt attttctgga 70260 tgaggaaact gaggcccaga gagggactgg tccttgtgaa gcatgacaga tgaggaacct 70320 cctctccctg ccttggcttc tctggttccc ctcctgcctg tagtcccagc cacccttccc 70380 agctgccttt tctgtaatat cttccttggc caatcagtgc tcagagttga ggtgggggtg 70440 gggaggcctc gagtcacgtg gtgggtgcct gcagtggcag cctgaggcag ggaactactg 70500 gatcaacctg tttggctatg cctccacctc tagaaacagc gatgtcatgc agaatgagac 70560 aagcctgttt ggggcctggg aactgtgtgc ccggctcact ctcccacacc ctgacccctc 70620 accccaagca ccactagtaa cagtcatagg agagccaagg ggccacacat ccttcagcca 70680 gccatcctgg gttcaaatcc catttctccc acttcctggc tctgtgaccc tggagcgttg 70740 tacttaaacc ttcctgtgcc tcatgctcca cagctttaaa acaatgacaa cgacggcatc 70800 acctagtaca gttggtgtgg ggactaaagg ggtaatttcc tagtgccctt aggacagaca 70860 gtgtctggca ccaaagaagt gccagctggt gctattaatt gtcattatca tagctctcat 70920 ttcttcttgt gtttgtttac cttgtgcatt taatagaata ctatttgcat ttagtagaac 70980 tactgttatt ctctcaattt tgctcatcaa gaaaccaaag ctcagagagg gaaggagacc 71040 tccctgagat tgcagagcaa gtgagctttg agcctgggac ttggagccaa gattgagatg 71100 gctccaggag cccaaagtgg aggggacatg ggcagggctc ctgagagtgt cacctctacc 71160 tgccctctct gatcctcggt ggagagcaga cacggttctc tccagcagct gtggaggcca 71220 ggtcagtggc ccagcacatt gctgcagtgc cttggccctc tgcctggagc tcctctcctt 71280 gcaaggctca tactgtcact tccctctttg ctgaagtggc cccttctcag caagacccgt 71340 ttcaaccctc tacttaatac tgaaaaccct tttttcagga aaaggagttt tcaggatgac 71400 acccgttttc ctcctttgtg gcttctgatt ctccttagcc cttgtcccca tgggacatga 71460 tttctgtttt acttatttat tctgtttatt atgaatggaa actccgtaag ggcagggatt 71520 ttattcctgc ccacttttat ttccagtggc atctccagca cctaaaacag tgctcaccac 71580 acggcagatg cacattaaat aattattgtg caaatattca ggcggcagga agggagggga 71640 gatggaggcg ggtggccagc tctggcctgt ggaagaggcc tctggtttgg gggcgtgggg 71700 gctggtgggg atcctcccgc ccgggctgag tctctgagcc tccaaagcct gcagcctaat 71760 gtgcgggagg cccccagccg cctttggcag gagcagccag gacttaccgc cccttggggg 71820 atcagtagga ttaaatttta atctgccttc cttccctgct ggttcctgga gagatggagg 71880 acaagggtct gtttttcgag ccagccggaa aacgcagctt ccctgccggg cagggcccgc 71940 ctggcagttc tgagtgctgg agtctggctc attatccatt cggagcacat tggtgaggca 72000 cccgctgagc gaggcttttc ccgcctcccc gcctcctggg agctgcctgc gtgggtgggg 72060 gccgggcagg tgtgcacaga tggcagggca gccatcaggg tggctgcagc ctgagagcag 72120 gagcagacgg ggtggcctgg gcccaggagg gcagaagcgt gacctggaag tgggtgctgg 72180 gaaaggcttc ttggaggcag cgggtgggcc ggaaggaggg cgttagggtg agggggcatg 72240 gcacaggcca agtcccagag aggggactgg cgtctccttt gatcttcaaa ggtggtgggc 72300 acgaggtagg agcctgttgg ttccgggaca aggcacgcac ttggaatctg gataaaacat 72360 acacagaggc agcgctagcg atgtgtggat acataagggg catttgtgca gcacaggttg 72420 ctggtaccgt aggaattcag gacactgggg aacagtcagg atgggcttca tagaggagac 72480 gggccttgag ctaggtcgac tggggaaagg tagaaggctg cttccaatag agatgtagat 72540 ggctcattca caaggtggag aggaggcagg attgatggaa gcggcaaccc cagttgctga 72600 gtaatgcgga aatcagcaga agactcaggt ccttgtcttc cagtttaagc gtcttaaaag 72660 gaaagtgttt atatgatgtg attaggactc agtgtgtgca cagtgtgatc gggactgagc 72720 agggcaaaga agaataatac cattaacagt caccgtgaac gtgaagcatt cagtagagcc 72780 ttttgggggt tttggcactc ctcatgcttg tttgtagggc ccagcatcag atcccctgat 72840 tgaagatttt cagagcagtg cttcagaccc cgtcctgtgg cctcagcatc ctgggccagg 72900 cccccacctc tggcctccat gcccggccac ctggtcatca aaactgcccc cagggtccag 72960 gggttctttc agattgtccg tttcagcccc gcgaggctgc tgcacgcgtc ctctgacctg 73020 ccgcttttcc tgctcgtcac ccaccctggg agagctctgc acggggctca tgggcatggg 73080 gctctgtttg cagatgagga agctgaagct ccgggtaggc cgttgccctg aggcactgct 73140 gcagccagcg gaggggcttg ggtgcaggac tgggggctcg gggcttcttg ggtgagtagg 73200 tgctgccccc aatctgcaga tgaggaagcc agtgtggcag agaaggggct aggatggggc 73260 ttccaggcag gggagaggct agggagtgat gagtgtcagg tctgtttctg tgctctagag 73320 gagagccgca tgtggatgta tgtgtggttt gtgtgcctgt gggtacacgt gtgtatacgg 73380 gtggatgtat gtgtggtatg tgtgttagat acacgtgtgc ctttggatgg ctgtgcatac 73440 ttgtatgtga atacttagag taagagtcag cttgtgtggg acgagcatgt ggtgattcgt 73500 gcattgatac agcacacttg ggtgtgtgta tgcgggcatg tgtgtatgtg tggacctctg 73560 gatggctgtg tgcacatgtg tataagcgta tatgagtcag catgtggggc ctgtggttat 73620 ctgtgcactt acacatccat gcatacacac gtgggtgcgt gtatgtgtgc aggtatacct 73680 gtgggtgctg tgtgcacatg cgtgaacatt catccacgaa ttggcacatg tgaggcatgt 73740 atataggtat tcgtgcatct gtgcacctgt gtgcatacgc atgtgttcac atgggtacac 73800 gttaggctgt gtgcatgtgt gtacaggtgg atgtgcgtga gatggcgggt gtggggcggg 73860 tgtggttaca tcatgtgttc acttgggtgc acatgtgtat gtgcgtgcgc cttgatgtgt 73920 gtggacatgt gtgtatgtct ttgcgtgttc ctagatcttg gcatgtgcac ttggtaacgt 73980 gggtctggtg ctcccgtgga cccgtctgca taggtgacta aggacttgtg tgccccagca 74040 cagctcctag gctttttggg catgggaggc ctggccacgc agacccagag tctctgcagg 74100 ggtgccactg ctcgaatgag aacgtgcccg gatctcagtt ggctggcgag agcccctaca 74160 gggggtggac gccacggtga gcggggccgc tcattggctt gagtccctag gttttccttt 74220 cctctcagag ccaggtgagc ttgggcagtg gcttctctca ggcttggcca cctcccctgc 74280 ggcgtcagcc ccacccacca cgatcagagc agagacctcg gcccccaaag gccaggaacg 74340 tgggaggacg tgcgtggggg cagtcgggtt tcagcgggat tgagaaaggc ctgtttccct 74400 tctcccccag gttggggctg agtcccctga attccagcct cccagccgga aggtggcagc 74460 ccagcctgaa gccctccttt gggccggagc agtccctgag ttttgccacc cttgggtgga 74520 gttagttcag ctctaacaag tgtgtcctgg cgtcccctgc aagctgggcc ttgggcccgc 74580 atggggaaga tgcagacagg agctcctgtt ggagcacttg ctgtttgcca ggaccagggg 74640 cagccaggga gacagtgtcg ggaggtggcc cccaaagggc cgaggagatg tggagatatc 74700 agccacggga atattggggt tggggaatgt tctagatggg agaggttcag gtgggaaggg 74760 tttgggattt tgcctagaac tgtgtggatt ggtgacctcc tatccaagtg tcctctccga 74820 gcctcagttt ccccatctgt aaaatggggc agcccctgca ccccagaaac aggttactgg 74880 gaggcttggc aatcctgatt gtggcttgga gagcagggag acagggcctg ccctctcatc 74940 cacctctatg gagggggcag agaggactcc gtgtccttgg aaaggccagg cacatccggg 75000 atgtggactg cttcccccat ggccctggag aaagtgccca ctgccctcaa ccctgtgctg 75060 ggccctgctg gacgatagca gcttggtggc cagcgctggc ctcttctggt cctggtggag 75120 aggcagggag gccctgggcc agctgcagcg acgtggagag aggacagggt tctgggctgg 75180 gaccggacag cctgcaggta caagaatgct ttgccccaga gaccgcctga gcgagggagc 75240 cagccgcact ccatttccag gtatttagac cattcctgag catccactgt gagccagaca 75300 ctgtccaggc actgtgggtg cagcagagaa cagagcaggc accttgctcc tcatggagtc 75360 ctcatcaggg gaggtggcca gtaagataaa cagtgggacg cagaccctta tccctgaccg 75420 catgtgctgt gaagacagcc aggtgggaaa acgagtggtc gagggaggtg gaccgccctg 75480 ctgcgggggg tcagggaagg cctctgtggg gaggggaggc tgagtcaaga catgagcaag 75540 aggcaggcga gagcatgtga agatgtgggg aacagcattc caggcaggga acggtaggtg 75600 caaaggctca gaggcagtag tggctttcag tgtgcagggg acagtgaggg gccagcagag 75660 gtcaaggtcc tgtgagggct gggaccctgt tgaccctggc gaggagtttg gatttggtgc 75720 tcagggtggc aggaagacag cagccgagga ggtgaggggg aatttttggc atgaggctga 75780 atctgtggcc tgcgtccacg ttccccagcc atgccacgtt ctagagggta tctcctctgc 75840 attcaaagag ggaagggatg acatgcactt cactttgctc cctgcagaac gtccttgcag 75900 aggtcatggg agtttggtac cctgggtgag tgtggccgtt tcgtgaatgg ggagactgag 75960 gccagactca gtcaggagac tcagattgct gagggttaga gcacagccga ctcccagatg 76020 ttgggcaggt gtgttgagaa aggccagccc atcttgggac agggctccac aggcccacct 76080 ccccaggagg ctgacaagca ggaccagaga agaccgtgga gcaggaacaa acccaacact 76140 gggagcaggg gatgtggggg caggaggtga aggaaacacc ccagagagac aggaggaggt 76200 ggggctccct gtggctttgg caggtgaaga aggggtcttc cttgctctct aggtgctagc 76260 tgtgtggccg tgtagtttct agtggcttgg ccctttccgt tggtatcact cttttatcta 76320 gatggacagt tgctgctgat ccccacagat catacacaaa ctcctattca tccctcaaaa 76380 cccagcctat atagccctcc tgttaccttt ttgggagagt gacttgtgcc ccactttcac 76440 acataccttt atctgcctga gcatactaat ctgctgttac tgctcttaac caacagccat 76500 tgtttgggtt tattccaggc aggggccagg tctcattcat tccatgtctc tccccaggtc 76560 ccagtgtttg ggagctgccc tgcccccatg ctaccccata cccagtcctt cactgggcct 76620 ggcttagggg ttctcccatc ttcagtaccc cagggcagac tctttcctgc ttcgagggtg 76680 tggctgggac attgactctc cgggtgatgt ctgcccccat ccaccggaaa tactagtccc 76740 aagcctaggg gtggtcctgc atgggacctg gcccttggct tcctctgtcc gtggatcctg 76800 gaggtcataa gaagggcttc ttccctgtgt tttgtttctg tgcctcagtt tcaccatctg 76860 tgagatgggg ctactcctgc ctgtacctcc catggcgctt atgcgcaatt gacatgttaa 76920 gaacacaccg tatgcccgac gcttggctca tggcaggtgc ttggagaagt gaccatcgct 76980 gtaatagttc tcccctgctc ttctggcccc cagccgcacc ttgaggctgc aggtctcggg 77040 gttttggctc agcctgaagg tggccaagag catggctctg ctcttggtgg gccgggctct 77100 gggctgtagg cggaggcagc tctaggttcc agcttgagcc cacctacata cctgctgtct 77160 ttctccgggg gctggggagg gggagtgatg ctgggctgcc acgccctcct ctctctgctg 77220 cagcccggga gcctgggcac ctccgccctg cgaggagatc ttggcaaagg ctgcgtcaaa 77280 tttttgttgg cagccacatt tcccagggct tggggtcacc tccttttggc caatctggtt 77340 tggggtcact ggggacagtt tcagtatggt gatggtgact tctgcggcct gtccgcctag 77400 tccttgccaa atactgagtg gctgccccaa tgcagctgag tcacagcagg ggctcgcccg 77460 cgtgccagcc tgtgaacacc catttgccag cacacacgca gtttagcctg gtgcaggggg 77520 cacccaaacc cacgcaaatt ctgcccctgc cctccgccac agcccccatg aagccacctt 77580 caggagcccc tccgcccccc acctccctgt acccggctgg cctgggctgc cctccaggcc 77640 tcctgtgagt ggaccctggt ggtcccaggc tgcgggctgg tgggcctggc cgaggcacaa 77700 tgtctgcctt cacaccgagg gccggggtgg gggcccggag gtccagccta ttgatggagc 77760 ggccaccgag ccctgcgcca catgttcctg ttttcctaat aagtccccag ttgtgagtgg 77820 ggaggaggcg gggaggcccc ggggcagccc agaaataatc acatgattgt gaaacacaag 77880 aatcctagaa agggtatctc cgagcgcctc tatctcaccc tgcctcctcc tcctcctcct 77940 ccttccctcg ctggctgcac tagctcnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 78000 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 78060 nnnnnngtat atgagtcagc atgtggggcc tgtggttatc tgtgcactta cacatccatg 78120 catacacacg tgggtgcgtg tatgtgtgca ggtatacctg tgggtgctgt gtgcacatgc 78180 gtgaacattc atccacgaat tggcacatgt gaggcatgta tataggtatt cgtgcatctg 78240 tgcacctgtg tgcatacgca tgtgttcaca tgggtacacg ttaggctgtg tgcatgtgtg 78300 tacaggtgga tgtgcgtgag atggcgggtg tggggcgggt gtggttacat catgtgttca 78360 cttgggtgca catgtgtatg tgcgtgcgcc ttgatgtgtg tggacatgtg tgtatgtctt 78420 tgcgtgttcc tagatcttgg catgtgcact tggtaacgtg ggtctggtgc tcccgtggac 78480 ccgtctgcat aggtgactaa ggacttgtgt gccccagcac agctcctagg ctttttgggc 78540 atgggaggcc tggccacgca gacccagagt ctctgcaggg gtgccactgc tcgaatgaga 78600 acgtgcccgg atctcagttg gctggcgaga gcccctacag ggggtggacg ccacggtgag 78660 cggggccgct cattggcttg agtccctagg ttttcctttc ctctcagagc caggtgagct 78720 tgggcagtgg cttctctcag gcttggccac ctcccctgcg gcgtcagccc cacccaccac 78780 gatcagagca gagacctcgg cccccaaagg ccaggaacgt gggaggacgt gcgtgggggc 78840 agtcgggttt cagcgggatt gagaaaggcc tgtttccctt ctcccccagg ttggggctga 78900 gtcccctgaa ttccagcctc ccagccggaa ggtggcagcc cagcctgaag ccctcctttg 78960 ggccggagca gtccctgagt tttgccaccc ttgggtggag ttagttcagc tctaacaagt 79020 gtgtcctggc gtcccctgca agctgggcct tgggcccgca tggggaagat gcagacagga 79080 gctcctgttg gagcacttgc tgtttgccag gaccaggggc agccagggag acagtgtcgg 79140 gaggtggccc ccaaaggggc cgaggagatg tggagatatc agccacggga atattggggt 79200 tggggaatgt tctagatggg agaggttcag gtgggaaggg tttgggattt tgcctagaac 79260 tgtgtggatt ggtgacctcc tatccaagtg tcctctccga gcctcagttt ccccatctgt 79320 aaaatggggc agcccctgca ccccagaaac aggttactgg gaggcttggc aatcctgatt 79380 gtggcttgga gagcagggag acagggcctg ccctctcatc cacctctatg gagggggcag 79440 agaggactcc gtgtccttgg aaaggccagg cacatccggg atgtggactg cttcccccat 79500 ggccctggag aaagtgccca ctgccctcaa ccctgtgctg ggccctgctg gacgataggg 79560 cgacggctgg ggtcgcggcc ggcgcgcggc tcgcggctgg ggggtagggg ctggccccgg 79620 ggagggggtg tgggacctcg cggtgccttg gggttttagg gcggtttggg ctggttgagg 79680 ctgggtgtgt gaccacgtcg tttttcttgg tcgactccgt cgctgagcgc gcgttgaggg 79740 ttgtggggtt gcccggcggt gctgccggtt cgcggggggt gtgtgcgctg gggcgttggg 79800 tatgctacgt gccgcggcac gaccactatc tcccgtttta tcgcgggtgt ggcctgtggt 79860 ttatttggcg gtatgcgggt gtgggggggt tcgtcccccc ctcgcgtgtt gggtgtgcgc 79920 gtgtggcttc ctgacggtgc agtaggggtc tgcgggtctg cgcctgggca ggtggtctct 79980 ctcccagccc gccctcgccc ctcctcaccc cagcccgctc tccgcacgcc ccacgtcccc 80040 cccagcattt cagtcagtct ccggttcgct ctaagtttca cagtcagtag tggctttcag 80100 tgtgcagtgt tcagtcaggg gccagcacag gtcaaggtcc tgtgagggct gggaccctgt 80160 tgaccctggc gaggagtttg gatttggtgc tcagggtggc aggaagacag cagccgagga 80220 ggtgaggggg aatttttggc atgaggctga atctgtggcc tgcgtccacg ttccccagcc 80280 atgccacgtt ctagagggta tctcctctgc attcaaagag ggaagggatg acatgcactt 80340 cactttgctc cctgcagaac gtccttgcag aggtcatggg agtttggtac cctgggtgag 80400 tgtggccgtt tcgtgaatgg ggagactgag gccagactca gtcaggagac tcagattgct 80460 gagggttaga gcacagccga ctcccagatg ttgggcaggt gtgttgagaa aggccagccc 80520 atcttgggac agggctccac aggcccacct ccccaggagg ctgacaagca ggaccagaga 80580 agaccgtgga gcaggaacaa acccaacact gggagcaggg gatgtggggg caggaggtga 80640 aggaaacacc ccagagagac aggaggaggt ggggctccct gtggctttgg caggtgaaga 80700 aggggtcttc cttgctctct aggtgctagc tgtgtggccg tgtagtttct agtggcttgg 80760 ccctttccgt tggtatcact cttttatcta gatggacagt tgctgctgat ccccacagat 80820 catacacaaa ctcctattca tccctcaaaa cccagcctat atagccctcc tgttaccttt 80880 ttgggagagt gacttgtgcc ccactttcac acataccttt atctgcctga gcatactaat 80940 ctgctgttac tgctcttaac caacagccat tgtttgggtt tattccaggc aggggccagg 81000 tctcattcat tccatgtctc tccccaggtc ccagtgtttg ggagctgccc tgcccccatg 81060 ctaccccata cccagtcctt cactgggcct ggcttagggg ttctcccatc ttcagtaccc 81120 cagggcagac tctttcctgc ttcgagggtg tggctgggac attgactctc cgggtgatgt 81180 ctgcccccat ccaccggaaa tactagtccc aagcctaggg gtggtcctgc atgggacctg 81240 gcccttggct tcctctgtcc gtggatcctg gaggtcataa gaagggcttc ttccctgtgt 81300 tttgtttctg tgcctcagtt tcaccatctg tgagatgggg ctactcctgc ctgtacctcc 81360 catggcgctt atgcgcaatt gacatgttaa gaacacaccg tatgcccgac gcttggctca 81420 tggcaggtgc ttggagaagt gaccatcgct gtaatagttc tcccctgctc ttctggcccc 81480 cagccgcacc ttgaggctgc aggtctcggg gttttggctc agcctgaagg tggccaagag 81540 catggctctg ctcttggtgg gccgggctct gggctgtagg cggaggcagc tctaggttcc 81600 agcttgagcc cacctacata cctgctgtct ttctccgggg gctggggagg gggagtgatg 81660 ctggcctgcc acgccctcct ctctctgctg cagcccggga gcctgggcac ctccgccctg 81720 cgaggagatc ttggcaaagg ctgcgtcaaa tttttgttgg cagccacatt tcccagggct 81780 tggggtcacc tccttttggc caatctggtt tggggtcact ggggacagtt tcagtatggt 81840 gatggtgact tctgcggcct gtccgcctag tccttgccaa atactgagtg gctgccccaa 81900 tgcagctgag tcacagcagg ggctcgcccg cgtgccagcc tgtgaacacc catttgccag 81960 cacacacgca gtttagcctg gtgcaggggg cacccaaacc cacgcaaatt ctgcccctgc 82020 cctccgccac agcccccatg aagccacctt caggagcccc tccgcccccc acctccctgt 82080 acccggctgg cctgggctgc cctccaggcc tcctgtgagt ggaccctggt ggtcccaggc 82140 tgcgggctgg tgggcctggc cgaggcacaa tgtctgcctt cacaccgagg gccggggtgg 82200 gggcccggag gtccagccta ttgatggagc ggccaccgag ccctgcgcca catgttcctg 82260 ttttcctaat aagtccccag ttgtgagtgg ggaggaggcg gggaggcccc ggggcagccc 82320 agaaataatc acatgattgt gaaacacaag aatcctagaa agggtatctc cgagcgcctc 82380 tatctcaccc tccctcctcc tcctcctcct ccttccctcg ctggctgcac tagctctgag 82440 gtaattgtag acaacccaac cagcttccag ggtgagggaa ggcatctcag ggctggcagt 82500 gtcggctggg ctggtgggga gcggtgccca cgtcgctggg ccctggggga gcgaggcctg 82560 cgcgcctgcc ggggagcagg cttcagtgga cccggcgcat ttgctaaaat cgaaacttgg 82620 ctggcttgct ggggccgctg tgggggtatt gaggctcctc tgtgtttttt tccagcgtgg 82680 ggagggcctg cagggggccc cgggcctccc tcccccgtgc tgaggatcag catgctggac 82740 tgggctgggc aggtgcccgc tgctccggga agcctctatt tataatctgt gtttttttgt 82800 tttttaaaaa aattcctcct cttcgccatc accctgcaga agaaggctga agctgcacat 82860 cggattctgg aaggcctggg gccccaggtg gagctggtga gctggggtac agggtcaggg 82920 gctcagggga gggcgggggt ggctggagag gtgggcaggg aggcgggagg gtgcggcgga 82980 ggaggaagtc atctattacc aagcgctgcc caggcggcgt ccgcggagga agcaggaaac 83040 ccaccttcct gatgagagga cggcagatag cgggtgggcg ggcctggctg ggctgggtgg 83100 gggtggggag tcttggcagc gagcgcctcc ggggccacct gcgcactcct gtgcataccg 83160 tgaagcccgg ccgctcgggc tgtgaggaga gtcacacatc cgtaggccgg tgcgcttgct 83220 ccagctgagc gcggagagcc ggttctctgg gtcacacaat ctcggtccac tcccaggtgc 83280 accgcttcat ggcggtgtga ccctgagcgg gtctgttacc ctccctgtgc ttcagtttcc 83340 tcatctgtaa aatgggaatc ctaacagcac ctattccact ggattacagt gaggaggagc 83400 tgtgttaata tttttccaac atcgggtgcc gcgcctgcct tgtaaacagt aagtgctggg 83460 cattagctat gatgatgatg atgatgatga tggcgatgat ggcgatgatg gctgtcacta 83520 gtgtcctttt gctgcggaaa gatgccatgt cagcagcaga gctggaaagc aggccccagg 83580 cctcctggag tccctgggct gaggatgggt ggatgcagaa gccctagccc ccagagaatg 83640 ggccgcagcc cctgcctgcc ccacagccat ctgtgcccac tgagctggtc agcatggatg 83700 gccgtggtgg gcactgaagg tatatgctac ccacatgtgt gccggatgag ggagagtctc 83760 tgtgtgcatg gtgggctagg gtgtgcgtgt gagtgcgccc agggtgcaga taaaggctta 83820 tgccttcgcc atgtgtagtg gctcatacct gtaatcccag tgctatggga ggccaaggca 83880 ggaggattgc atgaagccag gaatttgaga tcagcctggg caagatagca agaccttgtc 83940 tctgcaaaaa attaaaaaat tcaccaggtg tggtgatgca cgcctttcgt cccagctact 84000 tgggaggctg aggcaggagg atcgcttgag ccctggagtt caaggctgcg gtgagctatg 84060 atcacaccac tgcactccag cctgggcagt agagtgagac cctgcctcat aaaaaaacga 84120 aacagaagtc tgacaccttc agagcctcaa tctaaactca gctccactgc atgtttgcca 84180 agtggcctta ggaaaggggc tgacctccca gtaccacagt gctctctcat ctgggacagg 84240 cggaggctct agggcctcct tccagggtct tcccagggtt aaaggcagtg ctgcctgtta 84300 aaggctcacc tagtgcagct cctggtccct acgaagcgct cagtagttgt gaacaatttg 84360 gtgatgagct gctccccctg aagtttctgc aggctgctca gttttgcagt gagagctccc 84420 caaagcccgg ggtccgtctt ttgaggccac tcaggaacta caagccccgg gctcccaggc 84480 ccactcagaa ggcagaagca gggaggagat ggcaagggct cctccagctc agaagcaggg 84540 cccagctgcc cacctggctg gactcaggaa cctcgctggg ctcccccacc ccttcagggc 84600 tctgccccct ccaggcacat cctcgggcct gggcgatctg ggtggtgagc tctggcctag 84660 ggtcgtgctt ctctcagtgg aagtgatatc tggggaagtt ttcagcagca gcagctgctg 84720 cttgcttgtt tttttgtttt gtaaacagct ttattgaggt acaattcaca cgcatgccat 84780 tcactcaaag tgtccagttc agtgggtttt agtgtattca cagatgtgtg caactgtcac 84840 cacggtcaat tttagaacat tccatcatct caaaaagaaa cccttctgtc tctatggatt 84900 tgcctattct ggacatttcc tataaatgga atcttgcaat atgtggtcct ttgtgtctgg 84960 tttctctcac tcagcatcat gttttcgagg ttcatccgtg tcgagcgtgg gtcggtcctt 85020 cgttcctttt tgtggctgaa tcatatttca ctgtaggggt aggtcacgtg ttgtttaccc 85080 actcatcagt cggtggacgt gagattgttt gcatatttgg ggtattgtga ataaagttgc 85140 tgtgaacatt agtgtgccgt ttccatgtga acgtacgtct tcatttctcc tgggtgtgta 85200 cctaggcgtg gaattgctag atcctctgtt aaccctgttt agccccttga ggaactgccc 85260 aactgttttc caaagtggcc gaaaagtggc cgtaccattt tacatctcca ccagtaagct 85320 gcctcttgcc tcggtttctc cttttctgcc aaatagggat ggcagggttg gatgaagttc 85380 ccaagcattt ccagatttcc gggtcctccc gctcccgttt cctgattggt ccccgggggc 85440 ctcctggggg aaagggcctg tgtcttaggg cccgaggaac acaggcgagg aagcccctgt 85500 ccgtgggagt ctgtgggcag atgggggtgg gcagctgctg gtgtcagaag ctttggaacc 85560 agggacccca cagtgagtct tctctggttc tttggagaca aggggacggg gttgtcttcc 85620 acttggggat ctcagagcag aggcttccac aaggctgatg gcacaggagg ctaagatcta 85680 gtgtttggac tcttgaaggc ccctggcttg gtgccagtca gtggggacag ggaggacgcc 85740 tcacagagct gttgccgtcc cattttctgg atgaggctca gtgagaggag tgccttgtgc 85800 cgggccacac agcaagagat gaggcgtgga ggtgtgctga gcccctggga gagcggccgg 85860 ccagttctgc acagatctgc caggcccgag tggccacagg catcctccaa gcagaggcag 85920 ctgcatggtg caccctctgc agggtcctgt ctaccaactg ggtgccagaa gcccgggcca 85980 gggacggcct gaggtgctgt gggtcacaga gtccagttcc cagggtgtct tccatcagaa 86040 gctgcagttc caacgcccct cccctcggca gggacggatc cctgtggcct tcctggagga 86100 atttgcattg gaaaggatga aaatagcacc agaggtgcta accaggggtc gggggcactg 86160 agatggtggg gcacggcccc tccagcccag ctgtggggac tggaccaggc tgggagcggg 86220 cgcagtggtg gagggcgtgc ccagcagccc cgacctctct gccgctttga gtcattgctt 86280 ccttcctgtt ccaaggcgtt attttaagaa gctggtgtca ccagcgggtt gagggctggg 86340 gctgtcactt catttattgc cagctcaggc cgcctgggac tctggctctt cctggtggcc 86400 ctgctggctg gctcaaagcc cgaggggggc cgcctcctcc ctggcccctg ctggctttct 86460 tagtcaccac catgcctcat ctctgcctgc gccctgcgtc tggcacctgc tcccctttgc 86520 cctctttctg ccctctgagt ggctgtgcct ctgattttag aggagacgga ggctgagcaa 86580 gagagagctg gaccttgggg cctcctgggt gccgccccta ccaccccagg ctccacacgc 86640 atctaggcct cgattccctc actggcgtga gtccccccag gggtcatttc tcccgggagg 86700 ataaggcctg ggggtgaggg acaggggcca gccatgcccc ccagcctgtg tggctgtgga 86760 ggtgcctcat ggccccatgt ggggaccccg gctagcctgg gctgggagcc gccaggcctt 86820 tgtgcagccc tctctgcaga ggatgagggg gatgttgggg agtcccctcg ggccctgcgt 86880 cccctcagca atgcacctgc caggacatgt cactgtccct ccctcccccc actcccttct 86940 gggctttcca agatggctgt cctcagcctg ttgccatggc ggtgcacggc attccaggca 87000 gctctgggcc cagagcctcc cctgggctcc tggggttcag gggcctcggg gagtggctgg 87060 tgagtgcctc ccaggggggc agttcctgtt tagaggccgc agcaccccac agtatcctca 87120 gtccttcggg gccttcgcct tgtgggcccc tcaccgatgg ccgccttgag aagcaggggc 87180 tgtgtcccta tctacagggc aggggaggag gccaccaagt ggaagtggcc ttcctcccct 87240 gtggctttgg tgggttggag gctgaccggg ctcttgctgc ccccgggagc cggtcctgca 87300 tttctgcacc cgccctgtgc cgcagaagca ctgtcccctc tgcccacctc gccctcccag 87360 ggctgcgtgc tgtgggcttc cagccccttt ctggccccct tcggctgttt gctatcttta 87420 aaaccaaaac aagacaaaca ccaaatttca ccaagtctga aattttctgg gctatccaaa 87480 atttccgtga agtaggtcct ctttgaccta cacccatatt ccagatgagg aaaccgaggc 87540 tggagtgttg agggcacttg tccaagctca cagctagtga gggaggaggc accatttaaa 87600 ttggggccta tctgtttcca aaacccgaac ctttaagtga tgtccgcttg cacctggcct 87660 gcatttgatt ggcatgtggg gaacataaag gagccagtgt ggttgcccgg gttacagcat 87720 gggcatcttc acagggcccc ttgccattcc tgagacgagg attcgcaccc tctgcaggga 87780 tgctgcactg caccccttcc ctccactggg aagttctgca gtgagtctga ccgtgggctc 87840 tcttgttcct ctgcccactt ctccctcttg ttcaaacttc cagggtcagg gtggggaaac 87900 tgccctctgt tcagggctga gaaccttggg aggggagcct gacccggcac ggggagaaat 87960 ggcccatggc agctgcagga tgacatctct gtccccagga gagtagctga gcaggagcct 88020 ggaattgccc gagcccagtg gtgaattctc taggagggga tctggggcta cagggggaaa 88080 ggcgacattg tcaccagccg agactgtctg tgaggctctg tagagctgca gaggcccttc 88140 cctggggatg ggtgggcggg ggtctgggtg gcccactctg ccggcgtcat caggaggtgt 88200 gttcagctct atccccaggg aagagacttg tgtgtccctt ctgtcgctgc agccctgccc 88260 tgaggctgca ggactccacg tctccatcct tccctgttcc atctgatcac tcacactctg 88320 tacctgatct tcccaccata gtcacccatg gccaccctgg gaggctcctg ctgtgtgcat 88380 gggtgtgtga gagggagagg gacaggaaga gagggagaca gacagacaga aagacataca 88440 cacacacaca cagagactca ggcagagagg ggagcagact ccttcctcca gcgctggggc 88500 tgagaggcgg gctgtcattc aggctcatct cttaccagct gtgggcaaat gttgtaacct 88560 cttaaggact caatttttct ttctgtacag tgggggatga ttgtatcagt tacccggtat 88620 ggttacatgg ctactgctgg ggaacaaagc agccccacat ttagaggctt gaagcagcaa 88680 ctgttcactg tttctcacct gtctggaagg cagctgagca tttctgctgg tgtgggctca 88740 gctcttgcac ctccgtggcc agcgagggag tcggggggcc ggcgttgtag atcagcccag 88800 gctgggttgc accacgctgc tccttgcctc tctgcccgct tcctgcaggc caggctaggc 88860 tcattctctt gacagaaaca gcagaaatgc gaactcgcat cttcaagcct ctgcttttgc 88920 taagtgtgca gcaattccac tggccacagc aaggtcatgg gtggttacag ggaggcgtga 88980 aaggtgggtg ccattagcac agccactgct ccctgatggc ggcaatgtga ctggcacctc 89040 tgggcacttc agcctgcagg taccagcctg agagcttagc atgcactgtc tcgtttgatc 89100 ttcacaaaat cctatgagtt taaccccatt ttatagatga ggagaaatgg aggcacagat 89160 ggaataagta acttcccagg gagacccagc tagaaagtat cagaaccggg acttgaacct 89220 aggctgtgcc cttggttgct aagcaaggtt cttccatctg ggaggggaca cgtggcagct 89280 ggcttggtcc ctgcaccatc acagatgctg ccgtgctttc tgcgtctcct ggtacgctct 89340 ttgaagccct gtgcttgcta catgtgggcc ctgcctccct ttctcactgc tgtgtgggat 89400 ttgtggtgta accgagtcct ggtctcctta gctgctcttc tggtggtgga cggctagctt 89460 gcttctcact ggccgctgtg agcagtgcgt taggaacatc ctagcgcccg tctcctggtg 89520 gagcacagta ggcaactgca ggagcatggg ggtcggaagc gggggcgtcg gtgttcgtta 89580 ccaggtagtg gctgttgtct ctctggggga tgtgtgccca tacaccatgc tcccaccagc 89640 tatgtgccag ccttcctgtc accccagacc tcaccaacac ttggcattca acgtttttgt 89700 cttttgctgg tcagtggggg tggagtggta tcttgcagcg ttgggacgcg cgtttccatg 89760 gtgagctagg aagccaagtg gctttccacg tttggtggcc agggccaatc tctggggtgt 89820 gtgtgggttt gtccgggtgt gctctgggct gtggcccctt ccaggccagc actgctgaat 89880 gccccgcaga gcagccatga cgaccttggt gggggtggtc acagtaccca cagctgttcc 89940 cgaggaacca gtttcagcct gttcctggct ggggctgcgt gctgggtccc tgtgttctgt 90000 ttcatgcctg cctgcggctg agccctcacc cagaggacag ctcctccgtg ccagggctgt 90060 ggctcctacc ggtgggctct gtagtggcga gtggccagcc aggctctgat gtgcttctct 90120 ctctcccttt gcagccgctg tacaaccagc cctccgacac ccggcagtat catgagaaca 90180 tcaaaatgtg agtgctcgcg ggcagccgtg cagacacaca gaggcagggt gggcgagcag 90240 gctctcagca gcctgcatgg gatgtgggac gtgggctctc tgttcccatc aggggctccc 90300 ggccagggcc aggtgctccc ggaggggaca ggagacagtc ctaggtggca cctggggtgg 90360 gggtggggag cagagagagt gtccccctga ggttttggga gacaggctgg gtttgggagg 90420 gtgggcgagg gagctgctgg tgcacaggtg ggtctggaga gacggaggtc agaggtccca 90480 ggctgtacat ctgcatcctg ttcgagcagg agggagctgt tgcgggcaga aggcagccgg 90540 ctcagggaga tggggagtgg ccccagagca ggcgggggcc tggtgttttg ggctctggca 90600 taagcatgtt tgggaatcac ctggtgtctg cacagagagg tccctctggc acagcccact 90660 atggggcaga tcagagcact catccaggcc ctgaggcttt ggaggtggcc aatgtgatgt 90720 attctaatga tgggggcctt ttcccagacc ggtgctagga gggaagaaaa tgtcaattaa 90780 gtgccactgc cattgggtga ggcggtgctg gaggctggta gcattgtatc ttcaagcggg 90840 gtacaaggca ttggaggtgt ggcagctgga agggggctgg ctttttcttg ggatgcatta 90900 acgggagcat agactgttgg gccgaggagg gcatgttatc tcatgttagt gcccaggaac 90960 ccaaaaggta aaaggggctg cagatcttgc cccttgagga acatatggcc acgtggtggg 91020 ctggtaggtt ggaggtgaga ctcttcagga tcatagctgt tgaatgttca aggttcgtca 91080 tggtgagagg gtacaggcgt ttgagtgtgg ctgcaaaggg aggcgtttag ctgattcggt 91140 gggtagttca gcccggtccg attgttcaag cgttcctggg atggaactac agagtgtata 91200 tgcggtggtg agctccccgt tcctgaaagc gtgcaaacct tccagtgttt tcacacatct 91260 gctggtgctg gactagtcga cggggagatc gctgctgttg tagtttccag agttgcgcga 91320 ctggtccaag ctcaggtgat caacttggcc acctggtcat tgttgcagca gcctagaaaa 91380 tctctccttg ctagttgagg cccttggcct tctcgggttc aggagcacct gacaaagata 91440 cttcaccagc gtggctggcg ggggggtcat cctcagccag tggccagcag gggctgcaga 91500 gtgtgtcagg aaggggcatg tgttctgcgc caggggtccc gggctggtac agaaggccca 91560 tgtcagatgc agcctgggct cctcatcggc ctggcgggct cattcattgc ccaggtccca 91620 gatccctttt gactcgacat agtttgtctt ccaattgggc tacccctgtc ccttctgcag 91680 cttcctggga cctgccttgc tctggggccc ctgtctgggg tgggaagcca cagatggagg 91740 ggtgctgaaa gcaaggggga cattcttagg acctcatcac aggtggttta ggggatgagg 91800 gtggggtgtt ctcaactgag tccaggctgt ttggggcatt ccctcattca ttcatcccat 91860 ctttattgag agcctgctgt gtgtcaggtc ccgttctagg ccttggctat tcagccttgg 91920 ataaaacaaa ggcctcatcc ctcatcaaga tttgtctagc agtggagaca gaaccagaat 91980 gagttaagta aacaaaacaa gagaatgtca gctaatacag ccgggtgcag tggctcatgc 92040 ctataatccg agcactttgg gaggctgagg tgggaggatt gcctggggcc aggagttcaa 92100 gaccagcctg gccaaacata gcaaaaattg acaagaaatt agctgggtgt ggtggcacgt 92160 gcctgtggtc ccaggtactc aggaggcgaa ggagggagaa tcgcttgagc ccaggagttc 92220 agggctgcag tgagccgtga ttgcaccact gtactccagc ctgggtgaca gagcaaaacc 92280 ctgtttctgt taaaaaaaaa aaagaaagaa agaaaaaaga aagaaaatac cagcgaatct 92340 aaagtactat gctgacataa ctatcttaag ctctttacgc cttcatatac ctagttatga 92400 tttttctttt tgacataata atttttgata gccatattat tatactgaca attttacata 92460 ggtttttttc acttaaagtg agtgatattt taagctgaat actgtggttg atttcaggta 92520 ataaagacag ccatagaatc taaacaaaag aggagcaaga tgctcatata gatgacacca 92580 gcaaatagat attgcttcat ctttgtgtaa gtagaataaa actgtaagca tattaaagcc 92640 agtgctgtat ttgacatctc ataatcttcc tcagagaatg actgtggtcc gttgaagtgc 92700 attttgacta aataggtaac cgcctcactg aatttgttcc aaatctaaat cacaaacaaa 92760 catgtttcta tttaaaacaa ctagatgtgc tgggcgcggt ggctcacgcc tgtaatcccc 92820 gcgctttgga aggccgaggc gggcagataa cttgaggtca ggagttcgag accagcctgg 92880 ccgacatggt gaaaccccat ctctactaaa aatacaaaaa ttagccggct gtggtggcgt 92940 gtacctgtag tcccagctac tcaggaggtt gaggcaggag aattgcttga acctggaaga 93000 tggaggttgc agtgtgccga gatcacgcca ctgcactcca gcctgggcaa cagagcaaga 93060 ctctgtctca aaaaatatgt gtaatatagt ataatataaa acaaatagat gaataattaa 93120 gatttcctac actgtaagta gtcaacttct gttagaaaaa cctttgtgtg taaattgttg 93180 gaactgattt gtcctaataa ttttagtttt ttggatattt tctactaaaa ttatcatccc 93240 ttctattttt tagatttcaa tctggttatc attaaatttc attgtgcagt cattcatttt 93300 ttaaaaattc tattactctg gtaagtgggg taatgggaga gaaaatgagg gggtgacatt 93360 agccagagag gtcagggcag gccatgacag ttaaggggac ccttgtaggc tgagcagcag 93420 ctggctgtgt ggacctctgg ggagtgtccc agacaggtgg aacaggaggt gcaaaggcct 93480 tcctgagctg gcaggggtca cagagaaggc tggcatggcc caaggaggta ggcaagggag 93540 aggagggcac aggccaggtc acggggggct ggtaaggagt tccggtttta ttatctgttg 93600 ggataataat gatgaagttt ataatagtga tgaagtttat cccaggaagc aatgtgatca 93660 gacttttgtt ttaaaagttc actttggtgg ctgcagggag gaaggacctg ggggtagggg 93720 tgagaatacc atgggaaggc ccctgcagga gctgccgagg taggtagtga gcaccctgtc 93780 actgggaggt ttgcaagctg agggtgcata atgttcagga aatctgcagt gcccaggaag 93840 ctgcccttgg cagcctctgc accctgcact ccttgcaggc tctgatgttt tgtgaccgct 93900 catgctagac tgcagaaact gtctcgtgtc cagtgctggg acatgggaag ggaggccccg 93960 tgcaggcccc gtcccaccat gtggctggac acagggacct caagtgggac cgcagctcgt 94020 cctggctgtt tgactagctg tgtgtccctg tgggaagtca cttgccctct agggctcagt 94080 ttcagacgtg ctcactaagg tcagtgctca gcacgtacag cacatactac tgggtttttg 94140 gttcttcttt cttttgtcta cagagaccca gactcattca ttcgacaaat atttactgag 94200 catctactac acgccaggca ctgttctggg cctctaggag ataggagtga atgaggcctg 94260 acattctagt aggggaggct gataagaata aatacattgt gataagtgac tgccgccatg 94320 ggacaatgag atgatccagc cggggtcagg tggggctccc agcttcccct ggagcagcct 94380 ccctggcgct cacggcctcc tcgcccccgc tgctgtcatt gcttctaggt gggaggtcgt 94440 tccctcccca gagaccttgc cccgtcactt taatttctct gcgtctgcat gctggggccg 94500 cggagtgaaa gttaatttca cgcttgactt cctgccgcac agacgatttc ggacgcgttg 94560 gagtcgcccg tagccgcctc cgccgccctc ccaccgccac ctgcttcggg cgctgctggt 94620 gtcccctgct gcaggaggga gcgctcagac caccggggcg gggccggggc agccgcagag 94680 gggcaggaga tgggggctcc atcgagggat gggccccacc ctgggcagga tgctccagga 94740 attcccggga gtctatggag cccgcgtggg atgtggtgaa agtgcgtggg acctggggat 94800 gagcggcaga tggcgctcag gcacattctg cctctgcctg cccgggggtt gccctggttc 94860 accggccccc tcaggcctgg aagccggttt cttccgttgc tcgtttttct cttttcgcag 94920 cctgatttct tccctcctgc tgcctcattt gggggtcggc tgatgggaac tgtcagaccc 94980 ggggctgtgc aggcggaaag ggggatcagt cagaacccag gttactctta gcaggtctct 95040 ctggtcttgt tcagagacat cagatgactc ccccagggtc acacagacaa attcctagac 95100 cagtcctaac tgcacatcca gccaacttcc tctcctgggt ctctactcca ggccctgccc 95160 ctccctacct gggtgacctt agacaagtca catcacattg tttggcactg tcacagcttt 95220 tggttggcgc tcagtgatca ggaggttcag accatcaccc caacccgcag tctcttccca 95280 aggtatccgg gccctgcata tctgcctccc tcttcctctc ccctgcagcc ggggtcaggc 95340 tctccctgag caccccttct gccctctcca gattcactat tgctgcctcc ctccctagaa 95400 cccagggctc tgctcatttt cttcttccca ccgcattcct ctgcttctct caggcctcag 95460 ctcaaacctc ccttcctcca ggaagcctcc cctgattgcc cccaagcttt ccttttccag 95520 taccccataa accccaggac cagtcccagc tagggtccaa ccggactccc ctggaatact 95580 ctcataattc ctgcctcctt atcctgccct cctatgtcct gcttctcctc tccagtgccc 95640 tggcagatgg caagactagg tttccttata gggtgtgtgt ttttaaaccc tgacttcttt 95700 gcaccccatg agtgcctcta ccagcaaact catcacatgc tgcttacccc atgcctccag 95760 agccctccta cagactgtgg tccttatgct tgccggacag aagctcagca gaaaagattt 95820 gtctgcagta agctatttgc atcttcattg cctaaacact gcttggaaca aaataaacac 95880 ttaaaaaaac gtttgccaga ggaatgttga acacgtgggc atcataaacc aggagtcccc 95940 caggtggctg cctccaggag cgggaaggaa ggtttgagtg aggagggctg gtgtgaggca 96000 atagggagta gtaggggctg aggaacgggg agctgggcga cctttgaaag gagcagccaa 96060 gcctcagttt cccagcctgt ggccatgaag gggtgtggcc cgatggcctg atgttttcaa 96120 gagaagcttt aggtttggct ttttgtgtaa cagcctctgg ttttcagtgc tggcaatgaa 96180 tttaggattt tagaaagcac cagccgggtg cggtggctca cacctgtaat cccagcactt 96240 tgggaggctg aggcaggcag atcatgaggt caggagtttg agatcagcct ggccaatata 96300 gtgaaacccc gtctctacta aaaatacgaa aattagctgg gcgtagtggc acgtgcctat 96360 agccccagtt acttgggagg ctgaggcagg acaatcactt gaacccggga ggcagaggtt 96420 gcagtgagcc gagattgcgc cactgcactc cagcctaggt gacagagcaa gagactccat 96480 ctcaaaaaaa taaaaaataa aaaataaata aataaagcac cacagcccaa cacaacaccc 96540 tcagaggctg tctctggcct gtgcactgtg cagtttgcac cctgcggact tgacatgtgt 96600 ttgcagactt gacgtgtcct cttgcgtggt acgtggatgt ctctgggtgg caggcagtgt 96660 ccttgctttg ggaggaaacc tggatcagcc agggtggatt cacaccctca gttgctgccc 96720 atcggtggca aacagacggc tgcatgcaca tcaccaccac cccgaggcct catgctcacc 96780 gagtcgtttt ccagctgcag tgacagcacc gcggtttgtg gaagatcaca cgccggacta 96840 gcttctcagc gctgccttaa cactcggccg tgaaccgggc agctgaaaat ggcaggaact 96900 ttcttctctc acagtactgg aggccagcag ttggaaatca aggtgctgca ggaccacatt 96960 ctctagaagg ctctggggga ggctgcttcc ttgccggttc cagctcctgg cggctgccgg 97020 cctccttggc gttccttggc tgggagatgc gtcactcccg tcttttgtat tcgtgtggtg 97080 ttcttcccgt gtctgttcgc gtcatctccc ctccgtgtgt gtctgtcttt ttgtccaaat 97140 ttcccctttt cataagtcat tggattaggg cccaccccag taacctcatt ctaacttgct 97200 tctcgctcta aagactctgt ttccaaatga ggtcatgttt tgaggtgctg gggcttagga 97260 ctttacacat atcagttttt ttgtagttgg ggttgggggt gacattccca cctgtactag 97320 gcagtgtacc acctgcaaac cccaaagtca attttgtatg gtcttcacca cggtgtttca 97380 aagtggattc tatctctctt cttttgtgag aaggtggaac tatttatttt gaagtaacta 97440 gattgtacgt tgtgcaacag aagagttgca aatacgctcc acagagttcc cccacacacg 97500 tcacctggca cccctcatgt ggacagctta tataacagca gagaaacact taccacaact 97560 agggcctgcc atggtggccc acgcctgtca tcccagcact ttgggaggcc aaggtgggag 97620 gatcacttga ggctaggagt tggagacgag ctgggcaaca aagcaagacc tcatctctac 97680 caaaaaataa attagccaag tatggtggca tgtacctgta gttccagcta ctcaggaggc 97740 tgaggcagga ggattgcttg agcccaggag ttcaaggatg cagtgagcca tgatcgagcc 97800 actgcactcc cgcctgggag acagagtaag accctgtctc taaaaacaaa aatcaaaaca 97860 aaacaaaaca aaatactaag aaagaaatag tggcacatga ccctctgcta aactaccagc 97920 tgtctttgca ttttcacccg tctctccgcc aacgtctgtt ttctggtcca ggatctgatt 97980 caggttctca cgtgacattt gtgctcgtgt ctctttagtc tccagcccgt gacggcttct 98040 cagccttgcc ttgtttttca ccaccccagc acttttgaag atcactggtc atggctttct 98100 ttgacaggtg tttcctcctg gtaagactgg gatggtgggt tttggggaag accagagaga 98160 ggtaaggggg ctgcgtgatg cccacatgat agggggctct gccctaggtc tccgctgtcg 98220 ccttagagtt atccctcctt tgctctgttc tttactaggg agtcaccaag tcccacccat 98280 cttccagggc aggggagtta agctccgcct cctggaggga ggaatataga tttgtggagc 98340 caccgccatg attcatacat acttgcgggg agattctttg agactgtgca aatttcctgt 98400 tgctccttaa aattttgcca accaatttag cattcatccc cggatcttgc cagcggtggt 98460 tgggttatta ctgcgttcta atgacgattt tctgtttccc tcctctcttg gacatttatt 98520 cattggaact ctagaagaaa gatctgtccc ttctcctcca tgtattgatg tattgaatca 98580 tttgtttgta atcacatgga ctcgtgggga tttgttttat tcctgggacg ctaatctagt 98640 cccagggtta tttctgttgt cactcacatt gttccagctc tggcagccgg aaaccttcag 98700 gctgggttct gtgtcctttt gacttttgtt ttcttttgtt tttggcaatt cttgacttaa 98760 agtcactctg ggctcttctt gcatacttcc tggccgagcg ctggaatcag ccatggcccg 98820 ggcagcgcgg tttctgggat tggaggatgg tctttgctga gatatgggtg ctgctgtgct 98880 catggcgcct gggccttcac tgcttctagg ccttcacagc tgtcttttgc ataaaagacc 98940 aaaccctttg ccatgtcgaa actcacagga ccctgcagga ctggccctgc cagtcttgct 99000 cacagcccct cctccgtcct ctctgcccct ccccagcact gtccagccac agggccttcc 99060 tctgtctgtg cttccgatac acagagtttg ttcctgtctc ctgcggtgcc ctccagctgg 99120 agttcccttc cttctggatc ttcccagagc cgggtccttc tgatgacgta gatcccagct 99180 caaggccatc ctctctggga gatctttctg caccacggaa tctaaaatag cccctcacac 99240 cccgtccccc agcacccact agcccaccat tccatttaag ttcccaaatc caggattatc 99300 ttggtcatct tgcttattgt cagtgtcacc tctgtgagag ccctcaactg tgtcttgctc 99360 cctgctgtgt ccccagcacc tggaacagtg cctggcacat agtagatgct cagtaaacag 99420 ttattgaata acagaagatg aggctgcgat gccatagatt tcagatgagg aaactgaggg 99480 cttctgaggt gtgctcagag acaccctgtt atgagatgaa gggtgctggt cctagcctgt 99540 gggactgagg acccccatgg cccaccctgg ccggggggcg gcggccagac tgatggaagg 99600 tggggaggcc ctggccaagt caccaccaga atgacccggg gactgaggtg gattccaggc 99660 ccttgagccc catgaggctt cactcgtccg tcagagcctg gggttccctc cttttcctgt 99720 ttccaatggg gctggggtcc cgggggctgg acatagcgtg gctcccagtc agtagctttg 99780 gaacttttga gggggtttgg acactgctga gaatatgaaa aagttgggga tcccctcccc 99840 agaaaagcgg gtgccactga atgccgcgga ttggggacag acagcaagtt aaggtgcaca 99900 gcaggctcct gaggtcgctg tggcccccca ggccctggga ggccagctgc agcaccctgc 99960 tttgtgtgtt ggagaccgtg gggaggggcc tgggaagaga agaggacggt cctggggtct 100020 cggtgcagca gtgggtgggg gtgtcttcca gccctcatgg cgtgggctcc agaacctccc 100080 gcctctactc tccagggctc cctccctttg cctgtctcag ggtccctgtc ccctttcttc 100140 gggtcttgtc tctttccctc tccccacttc tctctctttc cctctcctag tttcatcttc 100200 ctctgagtct ctgtcccctt cctttggatc ttgtctctct gtgactgcct ctctctctct 100260 ctctgatcct ctctttctca tctctctcac tccagtctca cctctcagtc tcatctcctg 100320 tccatctcca ggtctctgtc ctttcttgga tctcatctgt ctatctatct ccgtctctgt 100380 gtctcccctt ctcccagtct ctgtctcttt ctcacctctg tctccctgtc tgtctcccta 100440 gtctctgggt ccctgtttcc ctctctgggt ctctgtctcc gtctctctct ctctgggtct 100500 ctgtttccct ctttctctgg gtctctgtct ccctctctct gggtccctgt ttccctctct 100560 gggtctctgt ctctctctct ctctctctgg gtctctgtct ccctctgtct ctgggtctct 100620 gtgtctccct ctgtctctgg gtctctgtct ccctctgtct ctgggtctct gtctccctct 100680 gtctctgggt ctctgtctcc ctctgtctct ggatctctgt ctccctctgt ctctgggtct 100740 ctgtctctcc tgtctctggg tcactgtctc cctctctctg ggtctctgtg tctccctctg 100800 tctctgggtc tctgtctccc tctgtctctg ggtctctgtc tccctctctc tcagggtctc 100860 cgtctccctc tgcctctgag tctctgactc cgggtctctg tctccctctg tctctgggtc 100920 tctgtctctc ctgtctctgg gtctctgtct ccctctctct gggactctgt gactccctct 100980 gtctctgggt ctctgtctcc ctctgtctct gggtctctgt ctctctctgt ctctgggttt 101040 ctttctccct ctctctgggt ctccatctcc ctctctctgg atctctctct ctctctctct 101100 gggtctctgt ctccttctct ctgggtctct gtctccctct gtctctgggt ctctgtctcc 101160 ctctgtctcc gggtctctgt ctccctctct ctctgggtct ctgtctctcc ctctgtctct 101220 gggtctctgt ctctctctct ctgggtctct ctctccctct gtctcagggt ctccatctct 101280 ctctctctgg gtctctgtct ccctctgtct ctgggtctct gtctccctct gtctctgggt 101340 ctccgtctct ctctctctgg gtctctgttt ccctctctct gggtttctgt ctccctctgt 101400 ctctgggtct ctgtctctgg gtctctgtct ctccctctgt ctctgggtct ctgtttctct 101460 ctctgggtct ctgtctccct ctgtctcagg gtctccatct ctctctctct gggtctctgt 101520 ctccctctgt ctcagggtct ccatctctct ctctctgggt ctctgtctcc ctctgtctct 101580 gggtctctct ctccctctgt ctctgggtct ccgtctctct ctctctgggt ctctgtctcc 101640 ctctctctgg gtctctgtct tcctctgtct ctgggtctct gtctccctct gtctctgggt 101700 ctctgtctcc ctctctctgg gtctccgtct ctctctctct ctctctctct ctctctctgt 101760 ctctctgggt ctctgtctct ctctctctct ctggttctct gtttccctgt ctctctgggt 101820 ctctgtctcc ctctctttct gggtctctgt ctccctctct ctctctgaaa ctcccgtctc 101880 ccaggacgtg cctccttctc ttggagcctg cagtggtgtg tgtaacctgc ttggttgaga 101940 ccccatgggc cctgccctga agtctgagac cgcccccgcc cgggggtttc ctgaagtcca 102000 tgcctggtgg ccccaccagc tgccccacac tgcttgtgtc cctccccccg cagcaggact 102060 gggtgtgctg gaggtccatg cacagcacct ggttggagcc aatcctgggg ccacacaggc 102120 cacactctga cacccggcct gtgggcggca gcaggtctcg gggtctcggg ctctgtggcc 102180 tgtattccta gttggaggct gtggctgttt ctccgtggcc atctttccgt gggcagatgt 102240 ggctgccggg gtgcatgtgg gcgggggcgg gaagccacag gcccctcggc tctgggaacc 102300 ctcttgcctg cacactgggc tcaacctaaa cgttggcggg ggctgcctcg cgcgcggggg 102360 agtaaggatg cacgttggca gctcacaggt ctctctgggg atacagcacg ggtgggtctc 102420 atctccctga gaaccaataa cggggcaaat ttggggctca ctctcagcaa acaggatggc 102480 acggggtgca gcgcctgagc ccggccgggc tgacctgtct gccgcttccc tcctgcacag 102540 aaaccaggcg atgcggaaga agctaatctt gtacttcaag aggaggaatc acgctcggaa 102600 acaatgggta agtccacacc gtggccccca tcagctttcc ttgagatctg gggagaatcg 102660 agcgcacagg gggccacacc tgccggggcc ctgtcagttc cgcagctgtg tcctccctga 102720 gtgtccaggc tgcggaggaa aagccaaggc cggccaggaa aggaggaaag acaacagctg 102780 cttccagaag gccccagggt gggtgggggt gggggggctc tatggcccct cttccagcct 102840 ggaagggaag aaagcaaaat gttggcctgg aaaattagtt gctaagccct ggtcacggga 102900 cctgtcctgg gcttttcagg cagaaagaga ggttttggag agaggtggag gatcagggtg 102960 ggctgtgtgc cgggcagcag gggccgcagg cgcaccctta caaatgagcc tttcctggtg 103020 cactgggccc aggtccaggc tcagggaaac tgagacagtg gacaagcatt gagccccctt 103080 tccctgagcc tgcatttgtg gccagtggcc tcatccaaac agaaaaggat gctgattcct 103140 gcttctcact gtaggctgtg gatctcagcc cacggcgggg aggctgggtc tgccagaggc 103200 atgtggtggt ggtttcaggc ggccgtggcc atcacccatt ccccggagga gatcagggtt 103260 gagtattctc ccagctgtca ggggaagaag cgcggactca gatgggcttc aacaggaaag 103320 gaatggctgt agctggaaat gtctgttggg tgtagatggc aggaatagtc tttcaactca 103380 agtcttgcct tcatttcatt tcattacatt tcatttcatt ttatttgttt atttatttat 103440 tatttatttt tgagatggag tttcgctctg tcacccaggt tggagtgcag tggcagggtc 103500 tctactcact gcagcctccg cctctcgggt tcaagcaatt ctcctgcctc agcctcccaa 103560 gtagctggga ttacaggcgc ccgccaccaa gcccggctaa tttttgtatt tttagtagag 103620 aaggtttcac tccattgacc aggctggtct tgaactcccg acctcaggtg atgcacccgc 103680 ctcggcctcc caaagcgctg ggatcacagg tgtgagcact gcacccagcc ccttcattcc 103740 tgtgcagttt tttcaactcc ttatgttaga acattgacaa actgaacctg aattcccata 103800 gcaggtggga gccggagaga gctgtgcttt ctcggatggt atcacagatg ctctgattag 103860 gccaggagag ggcctgcgtc ctgtgaacca gtggctgatg ccggggagat ggagtgaggc 103920 tgcctggttt tggctcatgg gactttctct acagttgggg atgatgtcat tgactccacc 103980 caagccacgg ggctgctggg acatggtagg gaatgggata aggctgggga ggccctgaaa 104040 aggtccccac ctggggaaga ggcgggctgg atggggactg ctgccttggg attcttggat 104100 aagagacgcg gcaagggctg ggaactaggt ttgctggagg ctggaggggc tcccctcata 104160 cctgcagccc cctgccccac ctcctctctc cctcagctgt gttgaggcag ggcctgcgag 104220 gcagctccct gtatcctttc tgggcctcca gagaggccct cccaggcgca ggcctggctc 104280 agtcatgccc agcgcctgta ggtctgtggt acacagtagg tgatgaccaa gtcctgcttg 104340 aactgaaatg ggccgggaca gggtgttagc tgatccagtg cctttggggc ctggatgcca 104400 gtagtcacgg agcacctact gtgtgtgagg ctcgcagttg ctgtgacacg ggccctgtcc 104460 tcagacctgc aggctgcagg gacaggtcgt gcgtaaggac gaggaggatg cccgcacacc 104520 ctgcccttcc ggtgcctgtt gtgttgcagg cgctcttctg agtgctctcc atacattagg 104580 gcatttagtc ctgcgaggtg ggcgcttggt cagccacatg tttcagagga ggaaatcgag 104640 gcacagagag gttaagtaac ttgccctagg tcacacagct gggaagtggt ggagctgaga 104700 tttgaaccca gaccacctgg ttcctgagcc catgctctga acccccaagg ggcagttccg 104760 agagagtcca ggagggtgtg tggggtatgg tggtgtggtg agcggccaca tggtggggct 104820 gagcagtgcc tggggagggg gaccctgggc aggcatgggg tcctgggcag gtgtgtgggc 104880 acgtggggcc aggtgagggg cttagctggg gcaggaggtc ctggctttgg aaggaggggc 104940 tgtgctatat gggaggaggg tcttcccttg gccctgcctg cctgctctgg ccccgaactt 105000 ggttgggtac tagagggagg agacacttcc agccagatgc tggtgcctgg gaagctgcgg 105060 gcagccctcg ggacccaagc cctgctcata ggtgaggaga ggtgggctgc ccagcagtgc 105120 cttgcccagc ttcctcagat cccccacctt gactggatgg tgcccacagg cacttgggct 105180 ggtgcgagag gctcttgaaa cgagcgtcca atctgtttat caagttaaga gatacccaca 105240 cagggctgct gggtgcccgg gagtcacagg ccaggaaaca gaccggtaat ctggggagaa 105300 gagctgcaca gagggctaga ctctcgagat gggctgggga cctcagtgct gaggtgggaa 105360 tgaccagaaa ggactggctt tgtgcggatc tgggagtcag ggtgtcaggc agagggcata 105420 gcaagtgcag aggccctgag gcaggaacca gcttgggaca gaacctggca ggccagcagc 105480 aggagccagg tcgcgtggaa acatctgccc tcaggctagg atggaacatt caggttttat 105540 tccgaatgca gtgggacacc gaatttattc ttaatacatg tatttgtagt aaagaatcca 105600 aagtccttat tctaagaaat ttgacagaag agtacaaggc acatctatat acccaccacc 105660 tagaatcagc cacggttacc attgccttgt atttgctctg tgtgtataac atgtttgttg 105720 ttgcactatt ggaaaatagg tgcagaggtg ccgaccttca cccctaataa atactccccc 105780 tctgtctcct gcgaggaagg aaatcctctc attttcacct aaaatgactg ccaattcagc 105840 gcgatcttgc cgcctccttg acagcccccc atggttcccc ccttggggtg aaggctcctc 105900 tcgggagggc aggagaggat ctgatttcca tttaaaagga tcgctgcagc tgctggaagg 105960 agctcaggct ggaggtggag ttggggtggg cttgagttct ttaaagatcg ccagtggctc 106020 cttggggggt ctgtggaggg ggtggaggga gaaattggct tatttaaagc tagagaagag 106080 gcaggcagaa accaaggact tccaagaagg gtccggtgtg gctttgtggc ccatcttagg 106140 agggatggaa acaaattcaa caccccctga agctgcggtg gcgattggga tggtctcttt 106200 gttgtggtat aagaagccga agtccctgac ttcattgatt tcagtaaggc ctggggaggg 106260 gggcttggcc gagaactctg atgtgcctgc ctcaccccca ctggggagtc agacccccct 106320 cagaccctgg gacccccaca ccttagcagg ttcctgggga cccccatacc tcttcccaga 106380 gagcagggcc tcgtccctgt catgggatcc tcagcaccag cacagccccc caagcctgcc 106440 acatctcctg ggaagctgag ctggaccctc tggaggccca gttggctgag agactggctc 106500 agcctgtggt cccagaggca tggctggcct gcttcttctc cctagtggat ttgcgctcct 106560 agcaccccgc agactagctg gcgggggtgg ggggcgggag ggggacggct ccagtctttc 106620 cctgtgtgtg tgtgtgcgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg 106680 tgtgtgtgtg taagacagag agagggaggg agggaaggga ggaagggatc tgtttcctcc 106740 cctggccagt gggtctgccc ttgtagaaaa atgccagtga gcatcttccc tgctacccag 106800 gccaggccgg agctgcccgc cctgcgctgt ccgaggcaga ccgaatgcac acccagcaca 106860 gtgtctngcc acaagtacag caggtgttac ctacagccgc nnnnnnnnnn nnnnnnnnnn 106920 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 106980 nnnnnnnnnn nnnnnnnnnn ctgaaaaccc tcaccagcca ctgccccgag cactttttgg 107040 ccgttgtctg tcaccagaac tgcctcttga tctccagcgc gttcctggca cagcctgcat 107100 gcatggggtt aggttctggg ccacccagca ccagcctggc cacctcgtgg ggaccgtcat 107160 ggtcacgggg ctgtcgagga tggagggcac agcttgccct tggtcagcag ctgaaatatg 107220 gggtggggtg gggctgaggt gtctgggctc caggaccaga gaggggcttt ctgactgtac 107280 cgaagcacca agtgggtgtt tgtggaggct cccagatcac accgtctgtc cacccccagc 107340 tgttagaggt ggagtaactg gggttgtgtg ggtggctcgc cctgcgtccc cttccccgcc 107400 cccacccccc gccccccgcc gccacttgct caagtcacct tggagatgtg gaagccaggc 107460 agctatgctc tgggctgatt ggggatctct tctcaaagga catgcagcag gcagcactgt 107520 ggttagatgt ggagagggac ttccttgtct tggagggaag gcagagcccc ctctctggga 107580 gctgctgggg tcctcacagc tggtccttgg ggtgaggctg gggaatgagg aactgcttgg 107640 aatgtggttt tctctggcgg ctgcccctcc ccagggctga cgggcccgca tgttgtacag 107700 cacagcttcc tgtggtgtgg cagtgggctc catccgggct gtctggtgcg gccggagccc 107760 cagccgcatg tggctgctgg acactggaag catggctggg gagaactaga gcccgactct 107820 taaattttac tggatttgtg atttcagttg agccacacat ggtgggtggc ttccatttgg 107880 gaccaggcct ctgcagagga ggccaggtct gggtggccgg ttcaccagga agggaggtga 107940 ccgtgtcctc aggggaagtc tgtgggtttt cttcaggggc ccccgtctgc tggatagcca 108000 tgcaactatg tgcctgtctt tctgtcgtct gcctgtgtga tgtgtgtgtg tctgttgtgt 108060 gtctacatgt gtgactctgt gtatgtgtgt ccatcatgtc tgcctgcgag accctgtgtg 108120 tgcatctgtt tgtctgcctg cgactgtgtg tgtgtctgtc atatgtctgc ctggatgacc 108180 gtgtgtgtgt gtctgcctgc ctgtgtgacc gcctgtgtgt ctgcctgcct gcctgtgtga 108240 tggactgtgt gtgtgtctgt catatgtctg cctgcatgac catgtgtgtg tgtctgcctg 108300 cctgtgtgac tgactgtgtg tctgtctgcc tgtgtgacca tctgtgtgtc tggctggctg 108360 gctgtgtgac ttatgtgcct gtgtatatat gtgtgtgtgt gtgtctctct gtgtatctgc 108420 ctatatgact gtctgtctgc ctgtgtgact gtgtgtctgt ctgtctgtct gcctgtgtat 108480 ctgtctgtgt gtctgccatg tgactgtgtg actgtgtgtc tactgtgtgt gtaccgtgtg 108540 ggtgactgca tgtgtgtatg tgactgtgtg tgtctgtgac tgtatgtgtg tgtatctgtg 108600 tgtctgcctg tgtgacttgt gtgtgcctgt atgtatgtgt gcctgtgtat atctgtctga 108660 ctgtatgtat gtgtgcctgt gcatatatct gtgtgtgtgt gtctctctgt gtatcttgtg 108720 tgtgcctgta tgtatgtgtg cctgtgtata tctgtctgac tgtatgtatg tgtgcctgtg 108780 tatatatctg tgtgtgtgtg tctctctgtg tatctgccta tatgactgtc tgtctgcctg 108840 tgtgactgtg tgtctgtctg tctgtctgcc tgtgtatctg tctgtgtgtc tgccatgtga 108900 ctgtctgtgt gactgtgtgt ctactgtgtg tgtaccgtgt gggtgactgc atgtgtgtat 108960 gtgactgtgt gtgtctgtga ctgtatgtgt gtgtctgtgt gtctgcctgt gtgacttgtg 109020 tgtgcctgta tgtacgtgtg cctgtgtata tctgtctgac tgtatgtgtg tgtgcctgtg 109080 tgtgcatgtc tgtgtgactt tgtgtatctg tgtgtgtctg tgactgcatg tgtgtctgcc 109140 tgtgtgactt gtgtgtgcct gtgtatatct gtctgactgt atgtgtgtgc ctgtatgtgc 109200 atgtctgtga ctgtgtctga gtatatgtgt gtttgtgtga ctgcatttgt gtgtgcctgt 109260 gtgacttgta tgtgcctgtg tgcttgtgtg cctgtgtgta tctgactgta tgtgtgtgcc 109320 tgtatgtatg tgtctgtgtg gctgtatctg actgtatatg tgtgtgcctg tgtgactttg 109380 tgtgtgtgcg cacgcacctg tgtgtctgcc tgcatgtgag tgggcagggg ggaggcggcg 109440 ggtgccaggt gcaggagcat cttccgcagt gccccctgcg ctctcccagg agcagaagtt 109500 ctgccagcgc tatgaccagc tcatggaggc ctgggagaag aaggtggagc gcatcgagaa 109560 caacccccgg cggcgggcca aggagagcaa ggtgcgcgag tactacgaga agcagttccc 109620 tgagatccgc aagcagcgcg agctgcagga gcgcatgcag aggtgagcgg ggcctgagcc 109680 cagggccccc gacgtcaggg cccggggtca gctccagcat cctcagtaga gatggcctgg 109740 ccaggaagga acagaacagc acagcagctt ctcaggccag tggccagggc cctaccagac 109800 cctggcctgt gtcacgtgga gcctctttgg cctaatactt acttggaact taaatacatt 109860 ttggggacaa gcacttcttc ccatgtgcca tagcgtgcac ctgccagctt cactcatttc 109920 tggggcctgc acgacccctg aaggcagctg agtttgagat ccctggtgtg ggacaaaggg 109980 gagagacgtg gctaagagac cacgctgtca gcctccccca gtggctgtga ggactgggtg 110040 ggccccatct gagaggtgcc tggtgacagg cagctgtggt tctatggcca tttttctttg 110100 gatgcacaga taaggcgatt cattggtaat gataacaaca cctttcaccc ttaactgaag 110160 tcacaagcca tgtctcatta agttccccac aacagctcta ggcagccagg tgccactttt 110220 gaatcctcat atgacagggg aggaaactga ggcacagaga gaaacacttc ggcccagggc 110280 caaagaggca gagctgggct ttgaacccag atctttgtag ctgggctttt cagggtgttt 110340 taggagagag gaagggactg agctgcccat gtcacagggt ttggccttgc tgggttgggg 110400 tgggggctcc atgcctcccc aggaccccgg gtgtggggcc ggcccctctg ctggccgctg 110460 cccacacttc tcctctgggg agggcgtggg ctcagggctg cgccacaggg gtctgctagt 110520 gtccccgacc accagaagac cggtcctgag tgtgtcccct tggtccccag cagggtgggc 110580 cagcggggca gtgggctgtc catgtcggcc gcccgcagcg agcacgaggt gtcagagatc 110640 atcgatggcc tctcagagca ggaggtgagt ccaggccctg actctggcct cagctccttt 110700 tccctggcat cccccgtgag ggtgcagagg ccctagccag aaaccacctc ccgggtggtt 110760 tacgtcgagg ggctttgcca ccgaagcgcg ggtggaatca aggtgggtat tgaggtaccc 110820 gtcccaggcc tgcaggggcg agcagagaga ggggtgttaa tgtgtctgag agggagggta 110880 gcaggacccc ctgcagggag ggccctggcg ctcccccatc cagatgccac aacagggagg 110940 gggttggggg acgaggaccc tgcctctcac tcttcccatc tcctgcctcc ttttggaact 111000 tcccattggc tgagtccagc cagaagccca aggggcggga gtgcctgtgg gttccagggt 111060 cagccttcca gggcccagag cctggcaggg tggggggagc atggcgcagg ccgaagagtt 111120 cccagcacgc cagctgtcca cgcagccacg accttctcgc aggcacctca gccctcctgg 111180 ctggagcagg gccggtttcc cctcaggcct ctttggggtg ccaggacacc ctggggtcag 111240 cctaggtgac cctggctgcc gtcactgggg cccacagatg gccaggaagc agagaggcag 111300 ccttttctcc tggggaggaa gttggtgtca gcctgttccc tcccgggtcc tgtgggtcag 111360 gtacccatga tgagactacc ccctgctcct aacaccacag cagacacgag gcagccacgg 111420 cacgtttctt ccttctgggg acttttgtcc agggagagct tttgtccaga tgggagatta 111480 tagcccttta gctcagcaca gcagagccac gcatggctat tgaaatcaaa attaattaaa 111540 atgggataaa attagcaatt cagttcctcg gttgcatctg acacatctca agagctcgac 111600 agccgcttgt ggttggcagc tcccctcctg ggcggagcag acagcgaaca cctccctggc 111660 tgcagagtgc tctgttggac aacagaacgc gctgccctgc gatgctgatg ctcagattag 111720 acagatggaa ggggccccag ggagggggcg gctggtttaa gtagcagttt ctcaccagag 111780 actctgattc agctggtctg gggcagagcc caggaatccg catttttacc cagccaccca 111840 cttgattctg acgcaggcaa tccaaagatg aatctggcca ttaaaacata atttttcatt 111900 ttaaaacttc tcgtggtacg tttttgttta caacaacatc cagttgacag aaaacagagc 111960 tcagaaagcc atcgcattgc acagccacag ggcccggccc tcgaaggctg ggcgccggag 112020 ctgggccgtg tcagcccctg tctcaccgat gctgtgcact tatggacatc ccgcagagag 112080 gctggctgtg ggtttagtct gcactggaag gaggaggccg gtggccctct cctctgcatt 112140 cctcacctga tggccaaggg tgtggcacct gggctgattg ttgcatgtac acacacacac 112200 acacacacac acacacacac acacacacac actggccaca tgggaatgca gtcatcagag 112260 tcctcaggga catcaaggat gctgtgtccg gggtgaaggg tggaagtgga atttgggaca 112320 gaaacttccc cagccagcct ggggtgacct gaggttcccc cgggagtgtg caagggaggg 112380 ggctgggccg gaggacaggc acttcccatc cttctgggag cttcctgtgg tcagagcaca 112440 tggccggcat gggaaggaca ggaaggcagc tgtgggaggg cagagcagag gtcctgcctg 112500 tggccgtgcc gggggtcctg ccattattac atccctggga tacccgagga aggtcgccgt 112560 tccgtatcag gggtgtaggg gacagctcca agggtctggg agacagatgc cagcctcttg 112620 gggggattct ctcccacccc ggggtcagag ctgtgccccg cacccgacct gacccctggc 112680 tgggagtcct gcacattgag tgaagaggtt ggatgtgggc ggccgggcag ctggatcgtt 112740 tgaactggct gaccttggct acgcggagtc ctcgcctacc tccggagatg ggtaattaat 112800 cgccagtaat tggctggctg cgagatttgg ggaagtgagc ccagctgagt ggcggctcag 112860 agcctcttaa tagtcatccc agtgcattag gagcggccgc ctgactcctg ccgcatgcag 112920 ggctgggcag gccagatccc aggtgggccc tctgaaggag cggggtgccg ggagggggcg 112980 tgtagtgtgg gggcaggaaa gacctctcca ccagcgaggc gctgaccctc tctgcgcccc 113040 tgggctgcct gcatgctgtg gggccagctg gaccccaggg cccactcttg cctgcggaac 113100 ctggaaggcc agcctgtctc ccgggctccc tgggcccagc tgggctgagc atccttcctg 113160 cagtgcttta tggcgcttgc atttccaaag ggaagattca tggctcccct cccactgcag 113220 agaaggcggc tgctgctctc tgcattgaat ctacagtcct gcccaccata aacctgtcgg 113280 ggaggccttt acattctccc ttcccccagc atgagctatt attattttta aactcatcat 113340 tctccttctc cttggtttcg cgttttccct gctctggcgc agaccatccg tcccctctgt 113400 gtcttccctg ggtcccctgc gccggccgga gcacctcgtc cctgggcctc tgaccctgcc 113460 ctccgtttcc ctgcagaacc tggagaagca gatgcgccag ctggccgtga tcccgcccat 113520 gctgtacgac gctgaccagc agcgcatcaa gttcatcaac atgaacgggc ttatggccga 113580 ccccatgaag gtgtacaaag accgccaggt catgaacatg tggagtgagc aggagaagga 113640 gaccttccgg gagaagtgag tcctccatca cctggcctgg cctcccggcc ccccaccccc 113700 atcctgttga ggcctgcgct gtctcccggc agccaccaca aatgagcatg ccggggggtg 113760 cttaaaaccg cagggattta ctctctcctg gttgtggagg ccggaagtcc aaatcctggt 113820 gtttcgtggg gttggttctt tctgggggcc gtaagggaga gcctgtccct gacctcttcc 113880 cagctggtgc tgccagcatc cttggccttc cggggcttct agatgcatcc ttccatgctc 113940 tgccttcgac cccacatgac ctttgtctct gtgcttctcc tcttcttata aggacacccg 114000 tcacactgaa tttagggtct agcctaaccc aatacaacct cacttcaact aattacatct 114060 ggaaagaccc tgtttccaaa taaggccgca ttctgaggtt ctgggtggcc atgaatttta 114120 agaggacaca cttcaatatg gtacaaagtg taagggcagc tggatgtaag acggggcact 114180 gcgagtcgga agaacaaggc aggagggact tagaggctgg gccgcagcct tgggcagggc 114240 ggcagctggc cagtggcttt tggtggtttc tattttgttt tgtctttgac aatagctgct 114300 ggctgagtgg gttcgtgatc ccatcactgt gcctgtgtct tctcagcttc atgcattttc 114360 cccctcctgt cccttatgac agctcagcca ggcccacccc agtacacagc tgatgacacg 114420 gaggctcaga gaggttcaga cagtgcacaa aggccacaca gcatgcacac aatggaggca 114480 gggttcagac tcctccagct ggaatggaga ggctgtatag ggaatggttt gtgaatgggg 114540 ccagggaggg gggctgtgca gagcagagac gggagtcgag ttctctcaaa agctgtgtct 114600 gagggggcca aaccccacag tgagaatctg cgatgtgaca tccaggcaga aggagacctc 114660 catccctggc ccggggtccc cagaggagat cgtgggccct gctgagccac cccacgcctt 114720 agggacagtg tgctataatt ccggggaatc taatcttttg gcttccccag gccacactgg 114780 aaaaagaaat gtcttgggcc acacagaaaa tacactaaca ttaatgatac atgatgagct 114840 aaaaaaaaaa tcacaaaaaa aatctcataa ggtttttttt tccttttttt ctttcttctt 114900 ttcaagacag agtttcgttc tgttgcccag gctggagtac aatggcacaa tctctgctca 114960 ctgcaagctc tgcctcccgg gttcacgcca ttctcctgcc tcagcctccc gagtagctgg 115020 gactacaggc ggccaccacc atgcctggct aattttttgt atttttagta gagatggggt 115080 ttcaccatgt tagccaggat ggtctcgatc tcctgacctc gtgatccgcc cgtctcggcc 115140 tcccaaagtg ctgagattat aggcgtgagc caccacgcct ggccaaaaat ctcataaggg 115200 ttaaagaaag tttacgaatt tgtattgggc cgcatttaaa gccgtcctgg gctgcatgtg 115260 gcctgtgggt tggacaagct tgctctaatc acttgcacgt agagggctgg gttccctgcc 115320 caggacatag agcacctcct caggacctca gagctctggg aggcaggaga gtgggaaact 115380 gaggtgtgga cggaggcctc tgtgcttggc caggagggga cgcagggaag agactttgtc 115440 actgcccgac gttcacccgg caggctactg agctgccttg gggaagaccc tgcctccgga 115500 caagagcttc ctccaaagca atgacactcc ttccccagtg ccctgggctt tggtccaggg 115560 ttgtggcccc aaagaggtgc caggcaggac ctaagggatg gggtgactct gggtccccgg 115620 caggggtgag tggacccgca agtgcagata ccgaactcag aaaggacaca gtggctatcc 115680 aggagggtct ttggtggaaa acatttttta agagtagctt ttgattatgg aaatgttgaa 115740 acgtccataa gaatagaggg gtggggtaat gagccctgga gtgcccacag caccgagtga 115800 gtggtccttc acaggaaaca gcgcttggtt cctgagcagg aatactcggt tacttaatgg 115860 ctcgtgcctg cagcctcacc atagcaggca cgatctttct acgtcaaatc aaagtctccg 115920 tcgaatgctt cttacagttt tgaacgaggg aggtgatggt gggacggtca cgggtgttaa 115980 gaattactga attactgttg cgtttgagat tcacgttccc cctggtaggc atgatgtttt 116040 agtgtatgta ttttttctga aatacaaaaa aaaaggtgtt ctgggagact ttctgcggct 116100 tcagcctttc ggaagatctc atgtggctct gcaggtctga taatgtcacc ctctgttaat 116160 tcagtaaccg aagggtgggg gacccaggct gggctgctat ctgccggccc gtggggctgg 116220 cgtaacttcc atcctgtgtg agccgcaact tggccacttg catgcctcaa ggactgtggg 116280 cttggtttga ggtctcatgt gcagaggaat tgatagcact cggggctttg aaaatcacct 116340 actgacggca tggggctcca ccacgtgctg gccatgtgac cattccccct ctgaacctca 116400 atttcctcgt ctgtaaaatg ggtatagcga cagggcctcc cttgtgaggt atgcagggca 116460 taggaaactt ctaataaacg tcttccaggg gtgcaagtga ggtattgagg gaggggaaca 116520 ggggacctag gagattccca agtttgattc ctggtctctt gggagccccc actgtgcctg 116580 gggaaacccc gtgggagggg tttgcaggga aggaaatgtc actgggacaa ggagagggag 116640 cggagaggaa aggactctcc ctacctggaa gagaagggcc ttaggatggc tccggccttg 116700 ccagccgccc gaggtgggat cccaggccag ggaagcctgc cattcctcac tgcgccgctt 116760 ccaccgggaa gagagcagag actgttcagg atcctcggat gtctggctgg gaagcaggcg 116820 cggggcctgc tggcctcctg cccagccatc tggagggcca ggcaggtcgg gcactggtgc 116880 tcactcagcc tccctccgtg ggagcccaca gtccagcctc actagcagcc agccgctgct 116940 ctccctgcga aggctgtggg gctgtggcac gtcgccggga cgcctgggcc tggggccagg 117000 gactccaccc agcacccctg gggtggagca ggccttgacc cacatccccg cccccaccat 117060 gctcccgctc ctttggccct cacatttcag cctgggccca gtggtttccc agtaattctc 117120 ctggctacgc aggaagccag ttgggacagt gccagcgacc cgccaccgcc ctccgactta 117180 agtccatgct tgccgcctcc ttggctggcc agccccctcc tgctgcccca cgggcactca 117240 gagcctctgc tcccagctct tctggggagg cccagcagcc tggtgagcta tgaccccact 117300 ggtggggccc tgccatgttc ccaagcagac cctgtgtggg ctgggtgagg ccctgcttcc 117360 cagatccagc tggagagaga aacaaaagtg gattttaaag gggggggaac cccaccaaag 117420 agctgcatgt cgtgtcctca tttttcctgg aagccgcctc cagcaggaca aacaaatata 117480 ttttcaaagg cgctaaagcc agtgactcac tccaaggaac gccctctctt acccctgggt 117540 ccccacccct cccgtctgcc gcagcagccc ttcccacacc cccctgggct taattgctcc 117600 aagtggggcg gtgcccgcca ggcccggcca gtggggatgg caggcgcctg ggagccgatc 117660 ggctgccccg caggaaagcc cccctcggcc aggtctcacg cccacccttc tcgtcccgca 117720 ggttcatgca gcatcccaag aactttggcc tgatcgcatc attcctggag aggaaggtga 117780 gtcgctgccc gccccatacc ccttcggtct ccacctccgt gggcaactgc gtggactcag 117840 ggtggaggcc ctccctcctt gcccacaagg ccctggcctg cctggcccct tgctccagct 117900 gccatgctcc cctcctccct ccctcccttc cttccatctg ggagatagat cagtgcaggc 117960 cccgccctgg cctcctgggc ccatggagga ggagcctcag gttgctgagc acctgggaat 118020 cccgagaacc ccagggagag ctgcacggcc aggcttcctg gagccccgtg tgcccgacgg 118080 gtctcctgcc agctcctcaa aggccacgtg gagcgtcctt gcaaactggg ggtggattct 118140 ggaagcacta cgtgcctggc atcccagtga agttttcgta ggcaggagtg gcgtgcctca 118200 aagggactgg agggaccagc ttttctaggt ccctctgagg gtcactgact gctttctgac 118260 acctctaatg ccaaaccaga cgtgtggcct gcaagtcccc atcttctttg gacaaacctt 118320 tgtgtggacc tgaggcctaa agcccacttt gtgtcaagcc caggcccgga gcagctccag 118380 gtggccggta gacacaaagt gtccccagag aatggtaaag ccgttgtttt gcacccacaa 118440 ggctggttgg actgtgcctg gagaggctgc aggtgggaga aggtggctgg atgaggctgc 118500 atgttggacg tggcccctgg gccttccccc agcatcttgg ggtcagagga gaaaggctgc 118560 cgtccgtgtg tcttaagcag cattcccctg aatcacgttt ctcagagatg gggacctgcc 118620 caccccagct tggtggacac cctgctcggg cttcctggtt gtaggaggga ggccaggagg 118680 atgaggcact tattttaaag gacagctgtt cccagcgcct gcccctcatg agctgataac 118740 cgtagaagga gagagaccga gcagagtggg gaaaaatctc tccatgcctg aaaaaccagt 118800 gtggagaaac aagccctata aatagcccat cttctgagtg acgacgtctc cctcagggag 118860 tggacggcac ggcggactct aggttagggc tccccaggat ggaagcattt cagaaactgg 118920 ccatcgagca gtcctccttc aggatgaggg gattagaagt ctttgtgctg gggagtaaac 118980 ttcatgatgt tctttggctg agaggcagcc caggacaagg cttcagtaga gcttccagag 119040 gggtctggag caggagctgc caacggagag gccggcgggg acagtcaggt cttgacagtg 119100 agtgaggctg acgtctggct gggagccagg tggaccagcc agtctgtgcc cgtctgcggg 119160 ggcagctgct gtccggagcc gggctgccat tgctgagcgc aggaaggagc tctcttgaat 119220 tgttaaagga gaagtcgggc acccacatcc cctgaattgc aaatattggc atctgattat 119280 aaaacgtctt tctcgattgc catgtttgtg ggctgggttt agcctggggc cgcctgggag 119340 cccccctggc ggtcgtactt ggcaggaggc tgccagctgg gggctttctg ttgagggcag 119400 tgagatttga ggcccagctc agaggcctca cagaatgccc attggaggtg gggtcctggc 119460 ttggcactgg ccagagcatt gcagaaacat tttacattgt aaggggaacg gctgtgggca 119520 ttggcaagct gggctccatg cccgcaagtg ggggcatcgt ggcatcactt tctgaggctg 119580 ccccttttac tcgtcccatt tggccggggt tcatggaggg ctggttgctc cggctttcag 119640 acccaatcta catggaaaag accaaggcag agaaaagaag gaaacccagg aagaggcgcg 119700 tggggcgtgg ggcgtggggc ggtcccgatg cacaaggctt ggaagaggct attcaggacc 119760 tcaaatatca gggaagagaa ggctgaagcc agggaaaaga gaacccggac ctatgtttgg 119820 ggaaggcttt gagtttgccc ggctgtgggc tggagtcctt gtttcccata agggctgggg 119880 gtgacatggc gacgtcagcg ctgtcattaa ccatagcaac agcggtgact gtgataacag 119940 gaaagacttc catcatgttt gctctgggcc aggcctcgtc ccaagtactt tacctatgta 120000 ttaactgatc tgatctttgt gataatcctg tgaagtatgt acaattagca ttcccatttt 120060 acagatgaga aaactgagac acagaggtta ggtcatctgt ccgaggtcac ccagccggta 120120 cgtggaagag gcaggatatg agcccaggat gtgagctcct ggctcctgcc ctgaatgcct 120180 gtgctgtacc ctgctcagcg tcctctttct ctgtcccaca gacagtggct gagtgcgtcc 120240 tctattacta cctgactaag aagaatgaga actataagag cctggtgaga cggagctatc 120300 ggcgccgcgg caagagccag gtaagaggca aggtgggggt gactgtcctt gcaggctccc 120360 tgcatgctca gcggccactt gcttggtggc cagcaccccg catggctggc ggtaactgtc 120420 tccatgagtt gttgttgctt ggccaccggc agtgtgagtg caggctcccc tccgtggtag 120480 cagcagatgt ggggagaccc cctctggggt gctcaccctg ccaggctatc tcgagcctcc 120540 cgtagtggcc aggaagatag ctggggagaa acagccacgg gcctcctcag cctgtgaaat 120600 cccagactcc tgactgggtg acctgtgatc tctgtgcgta aaaaggctac attccaaaag 120660 taagagcttc ccaggatgac ttggggtagt tcacaaactt catgtttaaa atgttaatgg 120720 ttgtgtgtgt ttatcttaat acatacttga aagaaaaaat agccagtact tcagctcgcc 120780 gttttttcag acgccgttgc ttgggatgag actgaaagat tatttacgct agagcagagg 120840 ctggcagact gggactctgg ggctaatccg gcccaccatc tgttcttgtg aataaagttt 120900 tattggaaca cagccatgcc tgtttgttta catattacca tggcagcgtc cttgctgctc 120960 tggtggagtt gcatggttgt gaccaaaagt gtatggcgta cagggtctca aatgtttact 121020 agctggccct tcatagaaaa agtttgcttt ttcctccgag ttagaggaaa aggagttggt 121080 ttgaaaaaat atccagtaaa taatggtaga gatgagaggc tcagtggcac gcctttgaaa 121140 gggggatcct gggcgctcgg tgtttgggag aatttgtttt gcatccgggc tcttgaagca 121200 tcgtctcaga gcagatgctg ggagcaccac acagaggagg cgggtggagg cagtgggcac 121260 tctggcagct gctggattgg agtcggtcga ggcatttcct tcctggggtc ctcagtggct 121320 ggggtggggg ccgggtgaga gtgacaaagg ccaagaatag cacgagccgc gtggagcgtc 121380 cttgcaaact gggggtggat tctggaagca ctacgtgcct ggcatcccag tgaagttttc 121440 gtaggcagga gtggcatgcc tcaaagggac tggagggacc agcttttcta ggtccctctg 121500 agggtcactg actgctttct gacaccccta atgccaagcc agacgtgtgg cctacaagtc 121560 cccatcttct ttggacaaac ctttgtgtgg acctgaggcc taaagcccac tttgtgtcaa 121620 gcccaggccc ggagcagctc caggtggccg gtagacacaa agtgtcccca gagaatggta 121680 aagccgttgt tttgcaccca caaggctggt tggactgtgc ctggagaggc tgcaggtggg 121740 agaaggtggc tggtactccc tatagtggca ccctctagcc cctccccaga gctgccccgc 121800 cttccctttc ccaggctgcc agaggtcgag acccataagg tgttgagacc agccatcacg 121860 ggttgggggc ggggtcccag tgtctgccgt gaaacagcca ctttcctaca gcctaagaaa 121920 actcccatga gggaaacgag gctgttgtca ggagcatgag ccacccctcg ccgcattccc 121980 aacatccagc cacgatgcct ggggctgaac tcggtcctta tccgcaggga tcgtggaagg 122040 gtggctgcgt ttgtggagag ggttttcttg tctagttttc tgtagccaga gttgaccagt 122100 ctgcttgccc ttctaacaga tgtgtaaaac caaggccgag tggcacagag catgtattcc 122160 aaagacgtag ctatgttcta tttttgtttt tttgggattt gttttttttt ttttttgaga 122220 tggagtttca caccgtcgcc caggtcagag tgcagtggcg cgatcccagc tcactgcaac 122280 ctctgcctcc tgggttagag tgattctcat gcctcagcct cccaagtagg cggcattaca 122340 ggtgcgtgcc actgcatcct gctaattttt tgtatttata atagagacag ggtttcacta 122400 tgttgcccag gctggtctcg aactcctgac ctagatgatc cacctgcctt ggcctcccaa 122460 agtgctggga ttacaggcat gagccactgt gctcagccgc tacggtgttt ttgaaattga 122520 agtgcattca ggaattttct agactgagag gcaaaaaggt aagtgccagt cagggagtat 122580 atagatgctg aggtatgaga ggcagcaggg agcggtgggg attatgacaa aggaagggtg 122640 gctaacggcc tcaagaggta tttggaaaac atcatcaggc gtctgttggg cccctactgt 122700 atgctcattc tcttgctggc cttcccagtt cccctcccat gacctgtttg ggggcattga 122760 ggctgggctt gtggtgggag cccttcctgg tagctgggct gggggctctg aagagcagag 122820 gcccatcccc tccccctgtg tgagagccac atttgcacag agggaggtgg ggagaccatg 122880 gtaatttaag aagggtgggg ggtgtcggtg cccggcatat cctgttgtag aggcctggcc 122940 tgtactgtgg tagagtgagt gtccagtaga gtgagtgtcc ggcttgctct tcgtggagtg 123000 agtgtccggc ctgctctccg tggagtgagt gtccggcctg ctgtccgtgg agtgagtgtc 123060 cggcctgctg tccgtggagt gagtgtccgg cctgctctgc gtggagtgag tgtccggcct 123120 gctctccgtg gagtgagtgt ctggtctgct ctccgtggag tgactgtccg gcctgctctc 123180 cgtggagtga ctgtccggcc tgctctccgt ggagtgagtg tccggcttgc tctcaggagt 123240 gagtgtccgg cttgctctgg gcggagcgaa tgtccagctt gctgactcat ccattgattg 123300 agcatttatt gtgtgcagga catggggagc ttcatgctgg ttgttcagag ccattgtaaa 123360 caggtggctt caagacagtg ccgcgggtct ccctgtgcgg cgggtctatc tgtgccacgg 123420 ggtctccctg ggccacgggg tctccctgtg ccgcggggtc tatctgtgct gcggggtctc 123480 cctgtgccac gggtctatct gtgctgcggg gactccctgt gccgcggggt ctatctgtgc 123540 cgcggggact ccctgtgccg cgggttctat ctgtgccgcg gggactccct gtgtcgcggg 123600 tctccctgtg ctgtggggtc tccctgtgcc acgggtctat ctgtgccgcg gggactccct 123660 gtgccgcggg gtctatctgt gccgtgggga ctccctgtgc cgcggggctc tatctgtgcc 123720 gcgggtctcc ctgtgccgcg gggtctccct gtgccgccgg tctccctggg aggtggcatt 123780 ggtggcacat ccttgaagac tccgtagaat aaaaggcccc aaagatgagg ttgaggagca 123840 gccccacagg cggacaggga tggggccctc aagtgcaaag gcagggagca tgagagacag 123900 cgcgtgtctt caggaacagc agggggcctg agtctttgga ttcgtggggg tcccggtacc 123960 tcccagggcc ttaaaggaac aaagaaaggg agattatgtg accctctttc ttttgctcat 124020 ttttgatggg taaatagaga tgtttttttt taccctgtga aaaatagaag tgcaaactcg 124080 ataaataaca gctcacactt gccttcgtgt ctggggaggg agtagggagt ggtgaggcct 124140 gtggctcact gcagagcttg ggccccgtct cagctccagt ggacgcttgg ccattggccc 124200 tgaattgcca ggtgttctga tctttgatga cgagctggaa atccagtttt atgtgaaact 124260 gcctgatttt aaatcttagg tcacattttt taaaaaggga aaaaacagct caacactgta 124320 tatgccacac aactcttact tgctgttgaa atcaccccca gccccaagta gaagacctct 124380 gggttagact acagtgagac caggggagga gggcattaga tgtctggggc caggctgggg 124440 caccggggaa gccctagaat gttccatagc agggaggaaa catgcccctc tttacaccgg 124500 agatgtcctg gtttagccgt ggtatctgcg gtgcctggga gttggtgggg ctttgctggt 124560 gagtttttat cccctgctga agctgccgtt ccaggcaggg gctcccagga tggggaaatg 124620 atgcttgtct gctctgcgtc tctcagaaag atggcagaaa gcaagccggg caggaggtcc 124680 ctgtctgtct ccagggctcg ccccttcctc ggatcagctg cgtttgctaa ggaggtggtg 124740 gcgtggcctg ggccctgcca ccccccacag gcctggttca caaccacggg gtaaacaggg 124800 gttctcaagt gctaactctg gggctgagag tcctctctgc cccatggcag caaggaaaat 124860 cagcggcagc ttcaggctca gcctgtcttg ttaagtggag atgcagtgac tgccgccagc 124920 tgagcgtctc tgtctgtggc tgtatttgtg gagccactga cactgctgat cagtctgccc 124980 caggtgaggg cacagcaggc ctggggtggg cccagcaccg ctgcttggaa ggctgcggtg 125040 acggacggga ggtgcaggca gtggtggtct ctgagtgcgc caaggctgtg agcacacaga 125100 acctgcagct ccttaaggag ggtggggagg tgaactgaga ccactcccca cccactaccc 125160 cgctgcctca gcatggctgg cacctgcagg ctgggacagg catctgggac tcttggtgac 125220 tgtgggctgg ggagccactg ccctgtgctc caggcaatgc aggcacccag ggtacctctg 125280 tgggccggtt cttctttctg acctatcctg gcagctcagg ccttgtgatc agatgggaat 125340 ccctggccat ggagcacacg agcccctgcc cagccccact cccctcacag ctgccccagg 125400 acacttgtcc atgcttctct ctccctcata ggtttctgag tgagcagaca cagccccttc 125460 cccctaccgt gacatgggcc ccctccccag gcaccacggg aagatggaga acccgggtct 125520 tcccagccag tgagcccacc caccctcagg ggtagggtgc ccactgccag gagatgctgt 125580 ctgcctcttc cccgatgtcg tctagtggga gggagctcaa gctcccttct ccgtgatgtt 125640 tacctggagg gcagcaggtc gggttctccc tcccttcctg ggccctctag ttttggaaga 125700 agacttaggt tatctcagcc aatatgcatt ggaccccttg atggctggtg ggggatggga 125760 cctgggagtc cagtgagaca tgggagcctt gtcaaaattc caggggcacc tggccctgct 125820 gtgtgatggg gatgggtgct gctggccgct atggtggcga tggcgatgat ggtgatgatg 125880 acggcgacag tgatggtgcc ggccaacagt catgcagcac tatcgccaca cactgtgatg 125940 atttcaacct cactagtgtt ggggacaggt gtgtaattat ccccactggc cagatgagac 126000 agaggcacag ggaggtgagg aagcttccaa ggagcctgct gagtggcaga ctgagggttc 126060 tagcctggca catgcagccc ggggagttgg agggaggccc agccgtcccc tcggcagcac 126120 actggccata aagccagcct tctggaagcc agccctgatc cgccaggtag gacaggcctc 126180 tcctgtggtc tgtgcaggag ccctgcgagg gcaggcggca gaggggctca tgatgaggct 126240 ccatgtcagt ggggagtcgg atgctggatg cggggacccc aggtgagcca ggctggatct 126300 gtgctgtgga gacaccctct gatatggggt gggtgggagt cctggggtgg ggggggctca 126360 gtaccccccg ccaccacctg tgtctcttcc cctgccatgt gtccctcagc tcctggggac 126420 agcagctggc cactgtctct ttctctctca gtgcctccgc cgttaccata tatgtctttg 126480 gggagttgct gagggctctt cctcatctcc ctctctcccg ccttgtctct cctccccatc 126540 tctgtctccc gctctgcgtc tcttgcgctc tctcagcacc cccactccca gtgcacagcc 126600 cctctctcct gggttgctgt ggaggctgct gtgggtggcc gcagagaggc tgtggtgctt 126660 gtggtcctgg cgcggtgccc gtggctccag gccacatctc tgctgaagac aggcacgagt 126720 ggcctctctc atgtcaccag gacagaggcc gctcgcaggg gccttcctgc ctcgtgtccc 126780 caagcttgct cgccccacag accccccagg aggtgcccat cggatgcaca gtatatgcat 126840 gttcatccgg gggcatttat tcagtgccta ctgtatgcca gggttgtcag actctacctt 126900 cagatgcgaa tccgacctta atccttccga aaatagggta aagggatcag ccgcgcctgg 126960 cccatctcaa caccccagac tgccctgatt ccacgctgca gaggtggaca cagggtagga 127020 cttccgaggt gtcggggagt gggcacgacc gcccctccca gggtcaacag cgcccacgtg 127080 cctcctgtgg gtttcctgag ttggggggtg catggcccag gaccaaggac atgggtgccc 127140 ctcctttcgc catttgtcaa ggtgggattg aaatggaggc tgtggtggga tcccgaggga 127200 ggggaagcct gtgggctggg ggtgagaagt gactccaggg acactggacc gtgcactttc 127260 cccggcagcg aggcttccga cttcctcaga caccactgac cacgctggga tggctgtagc 127320 cagcatcctg gggctgtgcc ctcctggagt tccccctgtc tgaggccaag gtctgctttg 127380 tgaggggacg tgtcccagtc tgagtcctca gatgtgagtg catgtcggaa tcaccggaag 127440 ggctggggaa acccagtcac tgggccgcac ccctcacccc acaataaggc cgagatccaa 127500 gactctgcat ttccaaggag ctcccaggcg ttggtctagg acgctgctga gaacctcggt 127560 gctgggggtc agcccctgag cagggagcag ggtggctgaa ggggttgtta agcccgaggt 127620 gggctacccc acagcccaga ccacccatgg gagtacactc aagctggaac ggcccttccc 127680 aggtgtttgg ggtgggcaac ggcctccctg gccagggccc aacttggatg aggcagctct 127740 gagctgagtt attgtcagcg cgcctgacag ccgatggcag ccagcccctt ctagaaggga 127800 ggtctggcca gtccagccca ggaggcagcc tgtgcatctg catgtttgca aagccacgct 127860 tcatagatgc tgtggccacc cgaatgctta accacagccc agcagcaaga cgccagtgcc 127920 accgtgtcat ctcaaggaca cctgccctgt ctgaagtgct tgcaccaggc ccttctccgc 127980 cctgtcaccc cgacaccatg tgccctgtac caaagcagtt tgtgtgtcat ttcgatggtt 128040 acgtttctga aacttggatg gttataaagt ggaatatgaa agtccttgat taaaagtgct 128100 ggccatggga cgtctctgga ctcagacccg cgctgtgtgc ggccgccttc actctggccc 128160 accttggcat ccatggcact ggtgcttagc cttgtggccg gctggaggcg agggatgtgc 128220 atggctgttt agagtggtgg gattgccttc ttgtttaatg gagggtgcca tcctctttct 128280 ggaagcttct ctgtgttctg acacggggat gcaggcccgg gcataggctt ttggaatgct 128340 agcccctcca cacccacccc catgagaccc cacaggcctg agctttggca agggagggcc 128400 gagcccccac ctcccggaac ctggcccctg agatcggccg tgagcggctt ttgagcctgg 128460 aggctgggtt gaggcccgag catcctctct tgggctccga gccccatcac caccaccctg 128520 aggtgaatca cggactgtgg ggcggtgcgg ggaacagctc aagcgctggc acagtggttt 128580 atagtccatg attcattgat ggaagggccg cgttatccta gtgaattgca aaaccagagc 128640 ccaggaatgc tggggcctga ctgcagaccg ttggggagcg aggatgtgag gctggctagg 128700 ccaggtggca gggcccggcc cctggtagcc aatatggcct tcccgcagcg atgggggttc 128760 atgtggccaa gggggcctct ctttctgcag agatgggaca ctgagacggg aacagcccgt 128820 cctgggctcc agtcatccgg cctgggtcca agaaggaagc ccagggaggc cgaggctccg 128880 cccccgactg ctgccgtcca ctctccactg ttccccatct ctgtccctct gggtctgctc 128940 tgcccaagcc cctggctctg aatctcctgc atttttctag gtttctctct ctctctctct 129000 ctctgtgtgt gtatgcgcgc acacgggtgg ctacgtctgt ttctcttccc atgtcttcct 129060 ccctctttct atttctctgt gtctttatct ctgtgtccac gtctcgtctg tttctctgca 129120 tgtgctttcc cgtctctctc tctttccccc atctaagtct tttaactctg tctctagctc 129180 tctctctctc tctccccttc tctctctccc ccatctctcc tcttcctcct cccccgcccc 129240 ctcccctcct caccctgtcc ctgggtctct cctctcaccc ttcctcctcc aggtctctgc 129300 tcctccccca cctttctccc tttctctctc ctccctccca ctacagcccc ctgtcccctg 129360 cctcctccgt ctgtcctctc ccagctcttt gcggagggac tggtgacctt gttccccttg 129420 ctgtggcact cggacagttt gcacagggaa cagtatgacc gggaaggctg ttccagggca 129480 ggagcagcca ggcttggtcc ctggggaggg gcagccgctg tgcggtgggt gttggtattc 129540 agggctagct gcctgcccta ggtgctgaag tcacttgatg gtggggaccg gtggcagggc 129600 gggccagatc accccaggct gtgtttcagc tcccaggccg agggcttgta tcttgtttca 129660 aacctgctgc ctgcttgggg ctgggccagg atgggcccac agccttccgg tggtgccgac 129720 tttcccaggc ctgccagagg aggtggctgg gtcctctcca gtcagggcca gctgggctgg 129780 gcaggattgg gtgcagtttt agggttgaag tgagcagatg tctctggttt cctgcccagc 129840 tttgtgctag gtggggagac agttgggggc tccccacgtc ctgcagtcag ggatgttgct 129900 cccagggaag gcagctggtg agtgggccgg agcccaggga tggagcagac cgggctgcag 129960 gttgaggaaa agaccaacat ggcctttgca tgggccagga tgcagtgcag gggcgatcgc 130020 atcagagagg cagaaggagg tggaaaatgt gagcgctccc caggcagcag atcggtcagg 130080 atcgaggggg cctgggggac atctcaagct gggctgctgg agtcaggaag tagttcccag 130140 aacagcagcc ttggtgtctg tggcagctgg aggcactgag ggaggggccc tggcaggctc 130200 acaggcggca ggttgtccct gggggatggg tggtgtttga gtctgttctg cagggatgtc 130260 attctaggtg attccctcgt ggacaagaca aacaaggtca ccccggtgcg gtggctcatg 130320 cctgtaatcc cagcactttg ggaggctgag gtaggtggat cgcttgagcc caggagttca 130380 agaccagcca gggcaacatg gtgagacccc atctctacaa aaaaattaaa aaattagccg 130440 ggtgaggtgg cttgctgctg tggtccgagc ttcttgggag gctgaggtgg aagcactgct 130500 tgagcccaga aagtggaggc tgcagtgagc cgtgatcatg ccactgtgca cctcagcctg 130560 ggcaacagag caagaccctg cgtccaaaaa aaagggcaaa caaggtccct ggagctgaca 130620 cccatgggga acttggacca tgtgcaagcc tccaaaaaaa agggcaaaca aggtccctgg 130680 agctgacacc catgggggac ttggaccatg cgtaagtcaa tcagcatggc aatttgagag 130740 agtgttgaag ggcaaacatg taagccaggg tcaggaggcc actgctgggc aggagggcag 130800 cttttatagg gagctggccg caaggcttct ctgaggaggt gtcccttggg ctcagacctg 130860 agtgataaga agggactggc caggcagaag tcgggggagc accccaggcc gtgggcacag 130920 cacgtgcaaa ggccctgaag caggaacatg cgggccatct tccaggagac aggtggtggg 130980 catggggaga gctgccctga gggaggtggg ccagggccag gaatcctggc ctcagagcag 131040 gagcagggac tgtggatttg atgccgagtt gcgggtcggg atctgaatta ggatttacaa 131100 cagagcctcg gctggcacag cacacatctg tacaggcgga acaggcttcc atgtgcgtgt 131160 taaatgttgc tcacgttctg tcgacacgca tctttctgcc gtagagtgct ggtaaatgtt 131220 taacaaccag ctttctgtag ggggaagctg cgtttgtagc atgtgccggt tgccatggtg 131280 taaataaatc ctctcaccgt gcccagtgcc acgtgacaac gtgctgccgc tgacttggaa 131340 ctggggaaag atgcccctag caccaggctg tcttatcctg ttctcaccct gtgcatggag 131400 ttggcggaag tcacctccac ggcacggatg acttcgtagc tccatgtagc cagatgatca 131460 ggaagcaatg cccttggagt gcttgtaacc ttcgctttct ttctttaaaa aaaatttatt 131520 atttttttag agatggagtc tcgctctgtc acccaggcta gagtgcagtg gtgcagttga 131580 agctcgctgc agccttgatc tcccaggttt aagctttcct cccaccttag cctcctgagt 131640 agctgggact acagggatgc accacctaat taaaattagc accaccagct aatttgtagt 131700 gacagggtct cactgtgttg cccaggctgg tctgaactcc gagccctaga caatcctcct 131760 gcctggccct cccaaagcac tgagattaca agtgtgagtt accttgccag gccataattt 131820 ctttaattgt aaggttaagt gtttccattt ttaataatgg ccatgagctg gtagccactg 131880 gctccagcac gccttggtat atcttttttt atttattttt gtttgagaca gagtctcact 131940 ctgtcaccca ggctgcagtg cagtggcgcg atcttggctc actgcaagct ccgcctcccg 132000 ggttcacacc attctcctgc ctcagcctcc tgagtagctg ggactacagg cgcccgccac 132060 caagcccagc taattgtttg tatttttagt agagatgggg tttcaccgtg ttagccagga 132120 tggtctcgat ttcctgacct catgatccgc cggcctcggc ctcccaaagt gctgggatta 132180 caggcgtgag ccaccgcgcc ccgccacgcc ttggtatatc ttataaaaag acaaccctta 132240 aacgcactga gatggcctcc cctgactgca ttttccccag caaggacagg agactgaatc 132300 cgagggacag agagcaggtg ttagggaaga gctgccagca acagggaacc ctgttctgcc 132360 tcggctctga cccctggccc cactttccac accaacccca ggctcctgga atccccatcc 132420 ctacactgcc aggaggtgga aggtgtcatg aggatgcgcc ctctcagggg cacctggcac 132480 atggtagatg ctcagtgaag tgtttgttga atgagtgcat gagattgagc cacagacggt 132540 gttgctgggt tttgggaagt tctcctgaca catttgtaag gacttagcat ctgagaatta 132600 aatctcatca acccctacgt gggtggtcgc agcaccttct cactggactg tctcctctca 132660 ttcccggaat ccaccgtctt ccttcctgcg acctgctatt ggattgctct ttaacatggg 132720 gtgggtcatg tgactccctg cgacccctgc accttttgag aaaggtcccc gggggctccc 132780 accgccctca gaatgcctcc tgtatttctg agcatgggtg ttagccctgg ccaggccctc 132840 cagccatgcc ccaaagtgcc acttggtagg cacaggggcc attttcccat tgccatgccg 132900 cagaggcctc ctgctctgcc aaagcccctt ccctcgccct gcatgtcagc acgccttgct 132960 gcctcatctg catcatgaat gtgccttttg aatgtgtcct cgtcaccggc gcctccatct 133020 ggcctgtctt tgtcaaccta aatacaagct ccatacagtt gggggccaca tctttctgtg 133080 gctggtgtgc cccttggggg ttcaggttat gctggcggaa ggaaagaatc aggcaatggc 133140 atcatttggt ttaaatgggc atagggagga ggctgtgaac ccccagccca gggcggaggt 133200 agggcacctg gctgtaggac cttctaggaa atgctgtgtg accttggatg agttacttaa 133260 actccctctg tctttgcatt ctcatccata aaactgggat gataccagtt gttgggagga 133320 ttcaaataac aggtaggaag tgattaggag aagaaggcct catcaaatgt gctcagcgag 133380 cttttgctgt ttttaattaa gatatttttc tgcatagccc ccagtctggg gcttctgcac 133440 aggcccagtc atgtgctgct tgtctggcag gctgagggtt atgggttcag tgtccagatc 133500 tgggggcagg tgtctcttgg ggctttgggc cagtggctct ggctaaccat agatccagta 133560 gggtttgtca cagagttgta ctgtggtttg gggggatgtt tctgaccacg cacagggcac 133620 aaacccactg tcagcctgac cagtggcaca tctgaaaggc agaggtagcc ctccaccacg 133680 agggcggggt cctttgagat agtggagctg gcttctagtt ctttctgatt ctcctttcag 133740 tcccctcacg ttgagggaat ggtgcccaca ggcgttttct gctgcacaga gtcctttatg 133800 tgccttgtga gacaaggatt cttgaaggcc tcactcctca gtgggatctg aggccagccg 133860 tggcagcttc tcctggcgca ggttagaaat gcagagtccc aggccccacc ccagaccgac 133920 tgagtgggaa ttggcagggg atgtgtgtgc acctgcaggt gtgggtaaca ctggcctgga 133980 gcagagtgct ctaacgaaag cccacaggcc aaatccggcc caccacctgc ttttgtaaat 134040 aaagttttat tggcacacag ccgtgccctt ttgttgatat aagggccgct ttcacaagac 134100 agtggcagaa ttgagaaggg ggttgacaga gacggcatac ttatcctctg gcccttacag 134160 aaaacgtttg ccagtccctg gtaaagcact ggttctcaaa tctggctgcc catcgggata 134220 acctggaatt taacatacga acgcctgggt ctccgcccag agatttggat gtcattggtg 134280 tggggtgcgg cctgggcatc aggacttcgc agggctcccc acgagatctg agtgtgcagc 134340 caatgtcatg ggaccttgag aaccatggcc cccagtggcc cgggaagccc agcaggtgca 134400 gttctgccgc tctatggaca ggcccaagac ccagcagccc agcctcgcca gtgtcggctg 134460 ctgcacttgc tgccctaaaa catagaaggc tttgggggct gagccggctg ccgggtcccc 134520 ccagctcctc agggggagtt gtgagctggg acctccctct ccctgcataa tctcccagca 134580 gcgagtatga gcggccctca atcagtccct cggcctcccg ggtggccact gcgagaccct 134640 gcagatgttc atcattaagg ctgccggggt ctgtcccact ggaaagcata ttttaaggcc 134700 agggctgctc tgctattcct ccttttcatc ttcccccacc ggactcactc agcgtgggct 134760 gcagggatgc ctctcccaca ggagatgttg aggccacagg aagtgaggag cctgtgcaca 134820 gggccctagg ccttggctgc agggtggccc agaaggtgct gtgctagtgg gtgttgctgc 134880 acccactcca accagagggt gagggtggaa ggcacccctg ccctgggggc ttgttaacat 134940 gtcagggaag aggaggcggc aaggcttggt gccaggattg cactcggtgc ctcagtttcc 135000 tgttctgtaa gatggacagg tgggtgggta ggggagacca tgtgggacgg agccaggcac 135060 gtggtgccat gagcgatcga atatggagac atagggggtg acgttccagg agcgaggggg 135120 ttgtgggcag gccctggcgg ggcttgtaga gtctggagtg ggaggcaggt agggataggt 135180 agatggggcg tgctggcaag tctgcagaac acaaactgta gatcctggct gggggttggc 135240 tgagactctc agcgggggct ctgggggcag cagggcccca tcccccacac tctgggccgt 135300 cagcctttgc tccgagacct cgaagctttg cctctctgag cctgtttcct cctctgcaga 135360 atgtgaccag tgatcactgc tctcctgttt ctgaggctgg gatagtgttt gcaaagcact 135420 tggcatggtg caggggtgtt actcgtggcg ttttcatctc catcaggact tcagaggggc 135480 caggagccgg cccatagaaa atggacagca cagtgctggg cacatagtca gctctcgggg 135540 atctgtgggg attttctcct ctgtaccagc ctcttcttcc ttggggcttt tctgaggact 135600 tggaggagag ctgcggtggg gaaggctcgt agctcagggc ctggcccaga tgcatccctc 135660 tcccaactgg cccctgcctg cggcctgatg ggtgtggagc tgcatttact ggccatgccg 135720 gagcagacat tagcctgatt cgttggtcca tgggtgaggc cccagggggt catggagccc 135780 ccaccagcct aggtgcaggg gctgatgggc agatgctctg ggaaggaggc tccgtggctg 135840 ctgctcccat cgggagggac gccacagccc aggtggggac ttcttggcac agacgtagct 135900 gaatgtggtc tcaggagaca ccaagcccgt gtgattcaaa agccccggcc ctgcccagac 135960 tctggccctg ggctgttgcc agggacatct gacccgggga gacggcatcc atgccgggca 136020 gcccaggggc caaggctctc tccccagcca gccacatcac tcctccctcc ccgggtccct 136080 acctctgccc acatcgggca aatgtggaca gaaaggatac tgtgtaggaa caagccaaaa 136140 aaaccctccc tgccccagct tccacctcca aaagaggctt cacctgccgg ctgtttaaac 136200 gttacgtttg agggttcgag gtcaggagag ggagaacagg ttgatcccag gatgccgggc 136260 acctgttggg gaatcagcag caacctgggg gccggggggt ctgttccagg tcgggcaact 136320 ctgccccttc ctggctcctc ttacagaaca tggtggcaag ggattcctgg ggaaaagagg 136380 cagatgcagg cccgaggctc tgccctggac ctggcagcag cctcagggag cccacggttg 136440 cctgcagcag tcagacactt gctctgtttt tctgccccat cctaaatgaa aagaggctgg 136500 agagagcgtt gtgtgcgggt caggcacctg ttcctggcag gaaggaaagg caagagaagg 136560 gagtctctct cacctccccg atccctcctc ttccatctgc ttggagttct tgctccctgg 136620 tttgaaacat tgccgtgact gtgcccctgg tacacattaa aaggctttgg ggtttatttt 136680 tatttcgctt ggctcagagg gatggaaaga tggtctggtt tggcagctgc ctgcagggag 136740 gaccttgggg tgtccaagaa aatcagtgtg tgctttaaaa gaaatcaggc gggatgacag 136800 gaaatcggga ggcggtgcca ggaggagctc acactccctc ctctatctcg gtgaggggag 136860 gggcggtagg cccagagtgg ctgggacagg tcggggaggc agatgacagg aagaggccca 136920 agtaaggagg ctggcttggc tcccagcctc tctgatctgc tctgtaaaat gggcttgttc 136980 tgtccccctg gggtgctggc atgcgaggga gaccaggccc aggcagcaga gcagccacct 137040 ccacgcaggc ctggggcctt cctgggctct ggggaatcag gggcatcccc ccacctcccc 137100 gttttacaga ctcggagacc gaggcttaga gaggtggcct gagctctgtc gggggcaggg 137160 cagggctggg gcatcagggg tgtgtcccca gcttcccaga tgctcaggca cccctgccga 137220 ggctcaccag ggcacctctc tcaacccaga tcacatctgc ccctcttaaa tatccgggcc 137280 agatgcggat gtaagcatgg tgaggattct ctcatttcaa cctcccagcc ctcagctgag 137340 gcacaggcat gctgaatacc cccattgtca aggcgaagga gtcggcacag agaggttaag 137400 accctcatcc aagctcacac agccactgtg tggaaagggc aggaattgaa gccagcactt 137460 ctgacaccaa tgcttcctgc ccctcacccc gactccgcct ccccaggccc ctagggcggc 137520 aagaccccag gccgtgcctc tccccatctc atgccagtgg ggcctggctt cccggttgtt 137580 tatgacctct tctgggtgga ctccacgggt tttcctcctc ctcccccagc tcaggctgag 137640 cccaggtgca gagattcacc tgttcacggt tttcttccct ccccactccc ctctgccctc 137700 ccccggggtc tgacagcagc agcaacaaca gcagcagcag cagcagcagc agcagcagca 137760 gcagcccatg ccccgcagca gccaggagga gaaagatgag aaggagaagg aaaaggaggc 137820 ggagaaggag gaggagaagc cggaggtgga gaacgacaag gaagacctcc tcaagtaagg 137880 cagcctgctg tcccctgcag ggcccggccg ctgacccaac ccgggtggca cacggttctg 137940 ggggaccctt tgtagagacg ggtggggtgc ccaccaattg cctgtgagca ggggggaggg 138000 ctttctgctc gtttgcccct gacagccccc cttccggaag cccacccatc gccctactcc 138060 tcctccctgg ctcccccctc tcctccgccc tcgctttctt tctccaaccc tctggagact 138120 ttagagactg atagctcatt tgagctccac tcctgagcta ataaatccag gcaatgactt 138180 tggaactctc tgcctccctg cttcctcccg ctctttcctc ctgaggcgcc aggaaggggg 138240 aaagggggat cagaggccct cctggaagga ctaggtgtgc aggcggctgc tgtcaccttt 138300 agaatcatcg atggcagtgt gagttcttgc agatcaaggc acagcctcac cgcgggggcc 138360 gtgacagcct cctgtgcctg ccaggggctg caggagtgca gccagctgga gaaagggggg 138420 cggcacgact tagcgccagg tacctgtaat gggctcagga atttggcttc agagaacatc 138480 tggcttcctc accccgtctc ccagacgctt ccagcaaggg cctttcagga agatgaatgg 138540 gaaggcagag gtgatcaatc tgagcctccc gcagtaaaac tctccccagt cacttctgcg 138600 agagccccag ctcgggtatc gaggttgtga gcacccccac acaccacagc taggcctgca 138660 ggctaggcct gcataaaacc agcaagagag tttcctcctg ccaatgtcta agatgatgcc 138720 cggcccttga taatactgaa ggccaatgta ttgcctctta tagagcccct ctggaaatag 138780 ctcctctgtg gcgaataaaa tggccctata aattgctgcc agcccacgcc cccatttagt 138840 tcaccaaata gtcttgcaga cagtatctct ctatttggtg cataaaatgg tcttgcagat 138900 aaccaccagc ccagaagaaa gtagccttgc aggaaagctc ccagtacctc ccatttgggg 138960 aataaaatag ccagccaatt aactacctgt ccacatggcc ttattggtga attaagttga 139020 tagcccaggt tacaccccca tcctttcttt ttcttttttt tttttttgag acagggtctt 139080 gttctgtcac ccaggctgga gtgcagtggt ataatcatgg ctcactgcag cctcgacctc 139140 ccaggctcaa gagatccccc taccttagct tcccaagtag ctgggaccat cagcatatgc 139200 caccacgcct ggctaatttt ctgatctttt tcttttgtag agatggagtc ttgctgtgtt 139260 gcccaggctg gtcttaaact cctgggctca agcagtcctc caacttcggc ctcccaaagt 139320 gctgagatta caggtgtgac ccagcacacc tggccgcaac tcccttttga gaaatagcat 139380 ggtgttgtcc tgccagctgt actcccactt ctggtgaaca tggagcccct gcagacttgc 139440 ccctggccac cctcacctca ggcctctccc cctctttcct agcgtccgat tagtgccatg 139500 gctggcagcc agtgcaaatc cagctaaaga aacagtctcc tccagtggct gtttgatttc 139560 ccggctcggg tgaagccatc ctatctcccc tctctggcct gtagggagaa gacagacgac 139620 acctcagggg aggacaacga cgagaaggag gctgtggcct ccaaaggccg caaaactgcc 139680 aacagccagg gaagacgcaa aggccgcatc acccgctcaa tggctaatga ggccaacagc 139740 gaggaggcca tcacccccca gcagagcgcc gagctgggtg agctgggggc cagggatgcg 139800 ggtggggaag gggctggaga cacggcgggt tgcgctcata tgaaagtttc gtgcaatttg 139860 agttaattgg caacagccaa ggggttggtg taagtcatgg ttggagtcaa atcccagcgc 139920 tacctactgg atgtgctgtg tggcccagca tgaattcctg aacctctctg tgcctcaggg 139980 tcctcatgtt ctcagtggga ggaatcggtg gttacctcta acgtgggggg acagttgtag 140040 tcacttgcta tgtgagaagc acctagaaca gtgcctgggg tgtaggaaga gttcagtggc 140100 ttcaaccaca gtgatttcag agcagggaga tgtcacaaaa aattcccagt gaccagttcc 140160 ggattttttg gttgtcgttt ttaaaacaga agatctggcc acgcttggcc caggttccca 140220 tgaggtggct gttgttggga gccgagtaac caccactcct tcttagaatg tcatgggctc 140280 tacttgtccc cacccagcct ctaccctggt aggcatctgg ttttgtacct tcacttccgt 140340 gggcctcagt ttccccttct gttgagaagg gtgttcatcc ctcactaccc tcccagaaag 140400 tagaaaaaaa tgagatgatg tgagtggcag ttcccaagat tcgccgcagg gggcagcggt 140460 gtgcgtctgt tgtctctact ttgtttagct gttagggtcc agccctccag ccactgcggg 140520 aacccaccca ggggcccaag cgctcaggcc gaagccccgc ctgccagggc tcattctcag 140580 ggtggagatg ctgcttcatc tcccacagac ccccaccgtc ccctggggtc cgggtcatgc 140640 acctgtctct tcttctcgtg ggatgtagtt tggacctatt tcataaatgg cccactcgaa 140700 gctcagagag gaaacgttcc ctctctaaaa atttcattgt agctggggtt agaactcagc 140760 cccattggcc acagagccta tgcagctcct gcagatattt tccagctgcc tcttggtggc 140820 ggtgtacttg gaggcccagg gtgaaagggc tttcttcctg cctgatctct ggggatagtc 140880 ctctcggacc caaggctgat gctgggggct cagccgcagg gtggaaaaca cactcctagg 140940 ccttccatgt ctcttctggc actgggcacc ctcagcaccc ctggcacccc tggcttctgt 141000 aggcttcctc tgggagtcct gtggggagga atgggagcat cgatgaggtc ccagagaggc 141060 ccaggctgtg gctgcagaga tgggggaggc tggggtggct ctggcctgtc ggggctgatg 141120 gggctgccca tgggggtggg ggccgtctcc cctcttctgc tggaaccttc cgccactcct 141180 cagccagcct ctgttggaca catactcccc ctggcgcagt tccaggtgct gagtccatgg 141240 agctgacgtc cctcgcaccc accccactca tgggtcttaa gcaactggaa aggaagggcc 141300 agggctcaca tccagaggag ctcggcagac agacccaaaa atagtgccac tgcagagatg 141360 cagccacctc cagccaaccc caaggccagg ttgtgtccct tcccagtaac accagaagcc 141420 cctccttgtc ctggatgagt gggggtatga acattccctc tggagcaggg cttctccgcc 141480 atgggcgatt ttactccccc actaggggac gccaggcagt gtctgtgaac agttttgatg 141540 gtcacaattg gagtagggtt gctggagtcc agcgtgcaga gtccagggtt gctaagcatc 141600 ctgccgtgat gggacagccc cacagtaata gaagagctgg gctccgagag ggtcctcggt 141660 cagatgaggt cccggcccac ctgaagcttg tgtcccactg tcgccacgtc accaggtgac 141720 ccctttccca acagagtgca ggcagaggca gtcatggtca aggcccttga ctgcttcagt 141780 gtccccttct ataaaatggg gtgatcgcag gtgccccgac ttcagcggct tgtgtggagg 141840 ttggccccga ccaacggcac gtgggactgc ccagcacagc tccagcccag cataaaggct 141900 cagggagtca ggtgccacgg tgggtactgg ctggggaggg gcgtctgaaa tgtggccttc 141960 ccacggggtt cagagccgtg cggtgacacc gtcaaggcct ggtctactcc ctccctggct 142020 caaaggagag aaaagggcag aaggcaaagt gcctcctctc ccggctcctg ccaataacct 142080 ggcatcttct tttcagcctc catggagctg aatgagagtt ctcgctggac agaagaagaa 142140 atggaaacag ccaagaaagg tgaggggtgt gtggcggctt taagccttgt tggtttgcat 142200 ccagggcgcc tgaagctcac gtgctgggga gggtgttgac acatttggcc ttgagccagg 142260 ggctgtggtg aggcctctgg tgaggttctg gttctgggct gttctcaggt ttgtcaccct 142320 ggagcctcag ttttaccttc cagaaaatgg gtctgtgcag ctgcgctgtc aggcttgtct 142380 ttgtgacttg agggcgcagc tcagagagac acagcttgtg ctgtgcatgt agtcagcgag 142440 tggcttctgg gtgacctctg tggccagcac ctctgggcct tggggacaga gcagtggcag 142500 cacacctggg tatctcggga cagtcagagc ttgccggcgg ccatctcggt agagtcctgg 142560 ggtcagggag acctgcaggg cgttcatcca gcccttagag ccccaaaggt cctatcctgg 142620 gctcaagtgt gctggggctt tggaaacctg tctcaggttt gagcacccca atctgggtga 142680 cgggttctgg agtggatggg gacacccagg ccgttgggga cagtcgtggg agtggctcac 142740 acggcaggga gccagcaggc attggtgctg gcagcagaag ccatcccgag cagatggcct 142800 tgtgatgtgc agcaccgtgg gggctggggt ccagtgcctc ctaagccgga tcccctctca 142860 gctgtgctgt ctcctggcca agatctttac ttcccagcac agtgacctgc ctctgggcct 142920 cggtttgccc gtctgttgag tgggagggtc gtctaggttg gctgtgcgga atcagataac 142980 cctgtgtgag ggcccatggt gggctgagtg ggagcgaatc tcctccctcc ctcggccgtg 143040 cctggcctgg ggcaggggct gtcggagctg gcgcatcact ggcagcactg ctgaggccgg 143100 ggcagcacct ggctcccacg gcacgctcac tctcggttat ctaagaggtg gggcctgctc 143160 ctgtccccgc ccatgtccct gtttgtgggc aaggagccag gaagcagagg ccaaggagtg 143220 ccacgggttc cggagctggt gtgtggggct gggagcaggc ccaggccccc actccccgtc 143280 cctgtcccgt gcttggtccc gtggccctgc tggagtcgag gctgtctgtg acgtgcggtt 143340 tctttgtgca gaaagctcca ggtcgtgact tatggaggga acaaaggccc tttatagcaa 143400 acgctcttgg cacataaggg caggtgtatc tgagaacagc ctggatcacg gggctcctgg 143460 gcccggcccc gtcctccact gtagttgtgg ggggtgctga gggtccccac agccctgaga 143520 agacccccac agcccccgcc ctcaccccgg gaccctgccc ctcgccctca gagctcctcc 143580 gggggcagtc tgccctccgc cccccaggct gaggtgaacc tggacccaga gagaccctcg 143640 caccattcag gaaggagggc ctgcctgccg ctgcaggtca ggctctgtgt gtggtgagtg 143700 agaggcatgc cagcggggcc tgggcactgt atccagctgg tagggcctgg gcactgtatc 143760 cagctggtag ggcctggggc tgctgtcagc ccccagagag gccacattgt tgtttctctg 143820 tctttaatgt ccacttggtg gtttctggca tgtatttcat tataggctgc aaaagaagct 143880 ttattgaaat tgtgtgattc ccgccgcctt ttatttaatt ttgagatgat acacatggca 143940 cgaagctcag cattctaacc actggaaagt gaacatctca gtggcatgaa gtacatctgc 144000 attggtgtgc aaccctcacc actgcctagt tccagaactt tttctcaccc cagatggaaa 144060 tcccataccc attagcagtc cctcccaggg ccccgcccca gccctaccag cccctggcag 144120 ccactaatgc actctctgtc tctgtggatt ggcctgttct gggcgtttcc aatgaatgga 144180 atcctacagt ttgtggcctt ttgtgtctgg ctcctttctg ggagcatgat ggttctgagg 144240 ttcatctgag tagctttgta cggctgaata atattccctc acctgcacgg accacatttt 144300 gtcggtcgtt catctcttgg gggatgtgtg ggttgtttcc atgtggctgt tgtgaagagt 144360 gctgctgtga gcatttgtgt aaaattgtgt gagattttta atcacaggtg agtccctggg 144420 atctcagcct gttggctggg agatttccca gagcacccac ccatcggagg actccgcgtg 144480 gacatcccca aacggtcagc ccagggtccc accgcctctc catcccttct cgtgtctcgt 144540 gttgtcacta ccacctcctc accggtgacc acccccgccc ccaccgccca ttgcctgaga 144600 actgggaaga cagtgcctgc cctctgtttg ccttctggaa gggcagatcc ggaggctggg 144660 aggacggctg gggatgactc accggcggag aggagcccgt gtcccaccat ctcaaggttg 144720 ggtcctcagt gatgacagtg agctcatcct gggtcctgcc catggagacg gcagtgagcg 144780 tcccctgggg gccgtgcacg cggaggccct gctcagtgac atttgtaata atgtcgtgag 144840 cagcagcatg ttcgtctgcc gtgaattaca gcaatctgga caattactgc tcagggtggc 144900 tgctaatggc tgtgtgttcc aggcgatggc aggagggagc gggggtgggg cggggagaca 144960 ggtgctggca ggccccagca actcctccat agggggtcgg ggtggagaag ctaggaacgt 145020 tctggagccc ccgcccagaa aaccaagagt taggaaaagg gactggagaa gcggctattg 145080 ctgaggcaga tggtctctgc ccatccttta cccatcattt cagcaacata gtgcctcact 145140 ctctgtgtgg caggggcact caggaatgag ccagccccac ccctccctcg gggagcctgg 145200 gcaggtaagc agccaggttt ccccagggcc ttcggacccc agcctgcctg aagcctctgg 145260 aagactttag tagcatggcc ctggaggatg agcagcagag gggccccatt cctagggaga 145320 aaccaggtct caaccccctg gatgtttcag ctgtgtgacc tcaggcaagt cagccaacct 145380 ctctgtgcct cagtttcttc atctgtacag tgggattcaa ggagcgccca ctgtatgttt 145440 cctgtggctg ccataataaa gggtcatgaa ctgggtggct taaaataaat gtattctctc 145500 actgttctgg aggccagaag tccaagttga aggcatccaa gaggctgcat tccctccaga 145560 ggctctgggg aggagcctgc cttgcctccc ccagcccctg gcgcctgcct gcagccttgg 145620 cagtccctgg ctcatgacca catccctcca ggctctgcct ttgtctttgt gtgcctttct 145680 ccctgcgtgt ctctgtccac attttcctct tcttacaagg acccacccca atccagtatg 145740 accccacgtt gacttgatca catctgcaaa catccttttt ccaaataagg tcacattcat 145800 aggttctggt ggacacaaaa tgttgggggg atgctctcca acccagcaca cccaccttcc 145860 tggggttttg gtgaaagtac acagaagagc tgagggcagt gctgcccggg gcataccgac 145920 ctccccatca ctttgtagct acaagcagct ccttagcccc ctgaccttgg cctggcccat 145980 ctgtttcacc ctcagttacc atcgttctct cagatgaggc agggatgcta cctcccaggg 146040 gcactttaaa gacggagcga gccacatagg aacagtcctt ggtatacagt aggcactcag 146100 aaatggcagg ccgctagctt agggcgcagt ctccagaccc tgctccctag gtttgggtcc 146160 cagctgtgcc tcctgcagag tctgaccctg agcaggtacc tacactttgg ggcctcggcc 146220 cccgccacct ctgtcttcgc cccggcgatg ggggtcggag gtaagtcacc tgccaagcaa 146280 atgtacagtg acaactggag gaacttccat ggtgctgggg gccaccagtc agagggctac 146340 cccgaggaag gggccgacac ccagagcacg aaataatagt gaatatcacc cagtaacacc 146400 gtggagccca tcctgcgtgc tgggcactgc tggaagcttt gtgtgtatga agtcacttta 146460 tctctaccaa cctgactagg aggcaggtgc tgttaatact tctgttattc aaatgaggaa 146520 accgaggcct agagaggctt agtgagcagc ctagggtcac acagctgtga agtggtagag 146580 ctgggatttg aacccaggca ctctacttgc agagtaggaa tggggttggc atgagagctg 146640 aacaggttag tccatgggcc aacctgttga ccaggtaaca aaggcaggac aggcatgtgc 146700 aaaggcccca tggcaggggc agtgtggccc catgagaagt ggttgaatcc cagaaggtag 146760 aggggccacc gggagcctgg ccttgccagc atgggatgga gtgtagctat tactctagag 146820 cgtgggaggc cactggggag gggctgggga catgatggcc atagggtttc tggtgggcaa 146880 gtgagcaacc tcccttcttg tgtgcatgcg gctgtggctg cctgccctgg ggcttgtgct 146940 gcctgaggac cgagaatgtt caggaggcag cttccccagg aaccgggcag ctccggggag 147000 ctggccgcct gccctcgggc ccagcgccaa gtggggaagg aggggcaggg caggagcagg 147060 gctgggatga gggactcggt tcccctggga aaggtcagcc tggcctggct tggaagcctg 147120 acccagctgt gcgagaggcc cgaggctctg ctggcagctc ctccaggccc cagccctctt 147180 ctctggcggg cagagaacct gctgtggagg gggttgggag gctcccggtc acaccattgt 147240 cacaccattc tagaccggga gttggctctg gcccgcctcc gggctgccag tccttcccaa 147300 tctccaggga gcggccaaca gtgggaggat gtgcaagacc aggccctggt ggctcccagt 147360 aagcccgggc agaccccaga ggcctccccc aggactccag ctgccttgtc tagtggcctt 147420 gccacttctc acaggagcga ggcaggaacc acccattgct gtgcacatgg gctggcctga 147480 cgggctttta tagatgaagc gtctaaggca tgggaagggg aggggtgagc ccccagcctg 147540 gagcctggag agcaggacct cctccactac atgtccactg ggaaagcctt gggctgtgcc 147600 caccatgggc cccccaaaag aggagcgcct gtgtgctctg ccgcacaaag ctgccagagc 147660 ttacagtggg gtgggcgggc cggtaggcag tgctgctgct cctgggtttg ggtctgcccg 147720 gctacttcct ggtgcagctg tccgtcaggg cccagcagga ggcgacactc gagctgtgtg 147780 actcaggagg ggtggtatac caggcaggga cggtgcggtg cctcggggct cgcgtccaag 147840 gagactgtca ccacgtgtgg tctggagaga gaccactagg gagggtgcat gtctggggct 147900 ggttggcctc ccggccggat atgtgagaaa cagtctgttg tgatggtttg gagggaggaa 147960 aaaattgggg tttctgcagg aacttggggt acagccagac acaggggcag ggtctggacc 148020 acactcttgc tcctgtcagc acccttgaag atgaaatcag gcatcaacaa gccccccttc 148080 cctcctaggg gagacccatg aatccgcatc cacatggctc ctgactcagg gaaggagcac 148140 ctggcggtcg atgcggtagt aatgatgcct gtcgtcacgt ggcgtggctg gtgctcacga 148200 acaaggcagg ccctccacac gcgtgtgtac acacgcacgc atacacacga cttctgcttt 148260 gcacaggaga agaccaaggc cagagggaga gccagtgctc acccagccca ctgcggtgga 148320 cacagggcat ggggtggtct gtctgacccc ccaggctggc ttccaacttt gctctgctct 148380 gtaggaaaac gtgacattga aaggtgtaac gtggcacttc cggaaatggt aggcgagaca 148440 gcgccaggtc gtatgcaggt gactttattt catcttaatg agtctgggtt tttttgagag 148500 ctgggagaag acgtagcttt ttcacatcgt acctatgatt tacgggtata attgctgatg 148560 cggaggctaa ggcagatagc gaggctgatt tttgaaagag tagatggaga gaaaagagtg 148620 gggaggtgca agtccaggtg tgatgttatc cagccaacat cctgatagga tttcaggatg 148680 gcaggagttc gggaagtcct gacaagacac gcaggagtgc ccggcctgtc aagggtgtca 148740 atgcggaggc accgtccctg tggaaccccc cccccgccag ggcttggggt ttctgaaatg 148800 aggaagtggc atgactcagg cccaagacgg ctgggttctt ttcctcccaa ctttgatagg 148860 gttttaggca gagcatgctg agtttctcgg ggaaaatggc aggtgggggg cggtggtcga 148920 tgcacccctc tggcaggcag cctgtgagtc ttcatggaag gggtgggaaa cgtcaaggct 148980 ggaggtgact ggctggggtg gggagagcga gtgtgtttcc agggttgggg gctgacttcc 149040 agagaaaaca gctgcaacat ccccagatgc aggtgggcgg tggtgtggtc ccctcggagt 149100 cctagctgtg gatgcaggtt tgcagaccct tggagaaaag cagcttggag gcatctgagc 149160 ggcagcacag gcctccctga gggccagagc acctgagccg aggaggctga gtcctggccc 149220 ccacaagaac agctcgtcat gggcccgcgg atggcatgtg ggacgctgcc ccatgggtgc 149280 ccagaggagg attagcccag cggggcccca agcacccact cccgtggccg ccgggcccct 149340 gcgcctggct ctccactcgg cgtctgtgac tcagacctcc tggctggact tcctgtcttg 149400 gtcaatttca cttcctagtt cctgcctcct gactcttcag aacgaaactc cttccttaga 149460 aattagaagt ggggtcgggg aatccagacc acagggcatg gtggcagaat ctgccatctc 149520 cgccctggca cagagtgttg ggggcgtgtg cctggatgtc aagggggata ccccagcctc 149580 ttttgggagg gttcggggcc ccctgcagag ctaaacgcac agccccctct tcctttgcaa 149640 gctccttacc agggacccag acgggtggca gagatgccca gggtgctcag caggccccgg 149700 acacctgccg atgagcagtg ggacgaggga gctaatttca gaggcggtga aagctatgaa 149760 gatgatcaaa ccctgggatg gcagggcgac gggggggggt cactttggag gggcgggcaa 149820 ggaaggcttc tctgaggagc catcacttga gccaagacca gagggaagac aaggcacatc 149880 tgtgagaaaa cccgtggagg cagcaggagc agctggtgca aaggccctgg ggcacacacg 149940 agtgacccag agagaggctg ggcgggttca tggagctggc tcctaagggt cacctgggcc 150000 gtgctagggc ctttggattt tattccaaga gcttcatgtg gtcactggaa gattttaagc 150060 agaggagtga tttcacgggg ttggcatcct taaaagtgca ctgagacctc ccctgcagag 150120 ggcagagggc aggactcagg tggagaggcc cagatccctg atgtggttga ggtttgttgc 150180 cctcccctgg catcgtgccc caggacgagg gctgggggtg cagggacatt ccagagacgc 150240 cttctgctcc ccagattttt agggggcagg atggaagggc tgggagttaa agggaaaagc 150300 aggttaatga tcccagagtc agggaagtcg gtcgtgacct gaatctagga tccaaagttc 150360 agctcagtta actttcaacc ttctgggtgg ctccccggca tttcccacag tgttccttca 150420 cggctgcagg ggctctcgga ggaggacgaa aggggcagct gtggtcccga gaccccccca 150480 gcagcagagg gctctttggg gaccccaaat ccccaaaccc ttccccctcc cctaaatggt 150540 tggcggtctc atgtgcaccc tgcaaaggct cctcaaatcc cgggatccct ccggaatgcg 150600 aggctagccc tgcccaccca cagtccccga cagagggctc ggtcagcctc ggcagcatca 150660 ggccaggcag ggggcagagc tcaggtggaa ctgacacgga gggtgggggg acgggcggcg 150720 ggggatgatg gcggaagaag ctgtttgctc cctgtctgcc gggggtggag aagctctgtt 150780 tttctggaac cctcatctgt tcttaccact gctgacgccg ccaccgccgc ggatggggag 150840 agagggaggg ggagccagtg ccaagttggc ccgccccttg tgaacctggg cctctgccac 150900 gctcccccgc ccgcctgccc gcccgccgcg agcctccgtc tggaggtcac attcagtcct 150960 gccgcgtctc gctgggtcag gcagcaagaa gatcagagct gagcccggct gcgggggaca 151020 cggctgccct gctgggcctg ggtccttgga ttttgcccgg cccgggggtc tgtgggctct 151080 ggccggcatt gctcgctgag cgtccgcact gggcacattg gtgctggagg agctcggcac 151140 gctgcgcccc ggtgatacct ggcccagggg catcccacac gcaccactga caacttcccg 151200 ccacccacca ccctcgggga agggcacctc gcgcgcccac agcggctggg ggacggcgtc 151260 agaggtggca ccgcccgctg aaggagcccc ggccaccacc ggcaggcgga cttgggagag 151320 ctgcctcccg gccggccttt tgaaccaagc tcggcccgcg ggggcctttc ctcccttgtt 151380 cccttcctnc cttngttcct tccttcctta angggggacg gaaaaagaat ggaggctaaa 151440 ctgaaccccc aaaaaaaccc aaccagaagc ccttaaaaag ccccccgggg gcgcgcccaa 151500 ctggcgggcc caaattggcc ccggccctgg ggggattttc ccccccccct tgtgttccgg 151560 gaaaaattgg cgccgggggg gagaccccaa agaagaaggg ttggggttgt ggggcctccg 151620 ggaggggggg agggaaatcc cgttctccgc cacgnnnnnn nnnnnnnnnn nnnnnnnnnn 151680 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 151740 nnnnnnnnnn nnnntcgctg agcgtccgca ctgggcacat tggtgctgga ggagctcggc 151800 acgctgcgcc ccggtgatac ctggcccagg ggcatcccac acgcaccact gacaacttcc 151860 cgccacccac caccctcggg gaagggcacc tcgcgcgccc acagcatggg aaaaaggaga 151920 agaaaaaaaa gagggggggg agggnnnggg ggggggaggg ggggggaaga gggagtaana 151980 aaaagcccta aagaaaaaag gaaagaccac agagaaaatn ntaaaaagaa aactccctcc 152040 ctccctccct ccctccctca ccgtgggacg gagaaggatg tgaggctgag ctgagccgcc 152100 agcagacgcc aaccagcagc ctcgcagagc cgaccgcggc cgcccagcct gccggcccac 152160 ttcggcccgc tccctggggc atcttcccag ccctatgttt ccggaaaact tggccgaggg 152220 ggagacgcga atgagaggat gtgagtgagt ggtcctgggg aggggatggg ggactgcggg 152280 tgcagggaca gggaccgcaa cgtggccatc tgggatttga ggctgggcag ctggggagtc 152340 ggagttctgg gcccctggag tggatggggg tcccagccca tcctttcccc catgccctct 152400 cctctctctc cctgctgggc tgaagctctc ctggaagcag gggtgggacc tggatctgtg 152460 cctgggaagg tctgtgatgc tgtgtgcaca gggggtctct ccaagtggac gggggcttca 152520 agctgggtct ggcggggtgg tctccaaggc acggtagggt agaaagtctt tctctccgtg 152580 cctggcagcc tctgcctggg cttcccagaa caggaaccag aggaagccag tgccagcctg 152640 cccctacccc gcagccctgg ccggcactaa tgggacaccc actctggctc ctcacacggc 152700 agttaaggaa actgaggccg gagagcagaa gggctggcca agactgctag cgagctctgg 152760 ccaggcgcct ggatgactct gcccagctcc tttgggagcc gtatgttttc aggaagggct 152820 gggtgacccc cacccccacc tccatcccct ctcctctgcc ctcaacccac tcccactgcc 152880 cccatgatcg gagttaatta gggtccccag cccccagcca ggctcctagc tacctcctta 152940 tttattgact gagtttggaa atgtcaacct ccccagtgtt gttgggccac cctcacccca 153000 ccccctgagc tctccatgcc caccccaccc agcaggccca gatgggagac ccgccccctc 153060 tcgccctctc ccacccgggt gccgggtctg tgatccctct ggcccggtgt gtttgcctgg 153120 gctctcttgg ccccggctgg ggaaatataa ataaacgcgc ggccctgtcc gccaggttct 153180 ggaagtggca gctgctgctg gcgcgggcgg agggaaaggt caggggccgg gtgccacttg 153240 atcccacgcc ccggccctcc ccttctgcgc ctgtccttga ggaaccctga ggagcgggct 153300 gtgaggccac gtggctccca gggccacggc aggcgaacag gtggcctgtc agtcagtgcc 153360 acccccacgc cacgggggcc agaggacccg gagggcagga agtctggggc cccacgcccg 153420 cgttgccccc cttggctggt cctctaagct tgggtgagtt ggcgggaccc tctgaaccga 153480 gatttccccc tcctggggat gggaaaatgg tcacagccat gacagcaagg atgagacgga 153540 accaagtctt tgaagggctt tgcaaactct gtgtgtcagt tagccgtgcc acgggctgat 153600 gtgttgatgt ttctgctgct gttgttttat ttgcattaga gccttgtgtg tagcaggcag 153660 gcagccagca cgtgggtggg tgggtgggtg gatgaatgaa tgaatgaatg aatgaatgaa 153720 tgaatgaaaa taccaacaca gacggctgcc cctcagctcc ccaacctctg aacaatttta 153780 gctggagctt ggcttgcagc ttgattttat tcaaggaaaa tggttaaaac cttcattatg 153840 ggaaatcctt cattaaagtc cttacaagtg gagctccagc tcagagaggc tgccatgtcc 153900 cgagctacgt gattcagcct tggggcctgc tgccctggag gggcaccctc ttgccgcaca 153960 gacccctagg tcaggagcac tccctgtctc tcccacagcc ctgggaaagt gggcaggccc 154020 tacctgcatg gactggctgg gccacacaag gtcacgccgc tggagacaca ggcataaata 154080 tagagctgcc tggcctgtgc ctgtgtgtgc cgcagctcgc cgggcagaca ggccgagacc 154140 gggggcttgg cttcccaggc actgcctccg gtgcagcagg ggctgtgttt ctgccgagcc 154200 tggtgtttgt ggccttgaaa ctagaacctg gggggcggca tgctctggtt ctggcctgag 154260 acctagtgat ggagggagct ttttctgccg attcctggag ggtctcttcc cacagcagga 154320 ggtctgtgag gctgagagaa cctcctggtt gtgcgggttg gggtttggga gcaaattcca 154380 gctgcgcaac caagcctggt gggccccgag tcctgagtgg gcctttaggt gcccttaggg 154440 agtttgggcc ctggaggtgc cccagttaac ctgggcctgg aggctcctgg ccccagctca 154500 tccccaccct gacttccacc ctcccatccc ctgctcacca cgtcccttcc tttcgctggg 154560 ccggtgtggc cggaaaacaa cccgtctccc gaggcctcgc ctgcagctgt gagcgagtgt 154620 cagggctggg tcacgtaggc caggccctcc gcccagcagg agaggtgggg cctgggcaga 154680 ggctgtgcgt tctggatatt cacagccctc cgcccccaga ctcccgcgca gtggcctcgg 154740 tgggacttca cctgtcgctt ttggctcctc cagcccaggc ctttcccatg catcctggcc 154800 tggagtcaag tgactgagaa accagacccc agaggccagg actgccaccc tctagtacct 154860 tccccgctag gggacacgtg gcccatcact gtctcttctt ccagaggtcc tgggcctgag 154920 cagggagccc caggctgggt ttctgctcca ggcccgtttg ccgcccaggc catggatgca 154980 ggccccctct gcgtgccggg cctggcctct tctcactgcc ctcctctcct gagacaggtc 155040 tcctggaaca cggccgcaac tggtcggcca tcgcccggat ggtgggctcc aagactgtgt 155100 cgcagtgtaa gaacttctac ttcaactaca agaagaggca gaacctcgat gagatcttgc 155160 agcagcacaa gctgaagatg gtgagccccc agtcacgctg caccgcgcct ctgggaagct 155220 gggagaggag cccagactgc ctcaggagat gtctctgcac cccaggaggc atgggccagg 155280 gaggggctat tatgccgcct tgttagaact cagcttctgg gggttcaagc ccgggagtac 155340 cccgagatgg ctgcaggcgg caatgctgct atgagtgtcc ctgccttgga gacgggccgg 155400 gccaggctgc cctccacccc caccctgcac cccactcctc tcagacagac acctctgggg 155460 gccctcagcc ctgtctcacg gtgtggggga aggagcgcgg tggaccagac tgactcagcc 155520 aggaattcgg gctgtcagcg cgttggaatg aggacccgga ggcaaatggg tcctgagcga 155580 gtggctcccc tgccccattt gacctcacag ctttagggct gccgtggttg gggagggaca 155640 ggtctggggg ggcgggggcg gacgtctcag ccccagcatc ctggagggct tgaggcaggc 155700 cacgggaggc tgagaccctt ccctcctcca caagcacaga aggtgcaggc tcgcctcgcc 155760 agcgtgtaaa tggcctctga ggagcagccg cttcttccac agctgtttct gggaattgag 155820 gagcattttg gggagacctc tgctgccttc cctctctcct tcccttcctc ctccttccct 155880 tcctccctcc tttctccctc tttgacacac ttgccaagca ttgtcccctt tttggagctg 155940 gggaaactga ggcttagcca ggctcatgtg cgactgaatt gcgatatgca cccacagtta 156000 tgagatcagc acccacgctc ttcatcgcta ggctgcgtgt ttcctcatcg atacagaagc 156060 actgagggag gggttgcata gctcccctcc cccaggacta ctcctccccc cgccactccc 156120 aaaccatgac atcgggctgc cttgtgcctg ggtgtaaagt gtgtgcagtg ggttccgggc 156180 aggccatgct gaattgctcc ctcagtgcaa cctgctgagg cccagagagg gtgagcaggc 156240 tgtgaggtca cacagcctgc agtgggagga ccaggtatag cctccccctg tttgaactcc 156300 gcccaagcac tgtgcagaat ttaaggacat ccttccaccc tcccgagtgg gttcttagtg 156360 agtcatgtgt gcgcgcggcc gctggtggct ccgggaccga ggggccacgg tcccacggcc 156420 ctgtggtcag ggctgagatc caccctctgg cctcagggag gcccctcccc atcacttcca 156480 gttaagcagt gccccgcgtg ccctccacat tggcccctgg gatttgtccc cagagctcag 156540 ggcttcaggc agcgcctttt ccttctggat gcttcgggcc ttctggttgg gtgtggagga 156600 aggcaccgca tctggctgaa tgtgcagaac cccgtcccta acacttgctg aagtcccttg 156660 tggcaaagag ggcctgagcc agagcagcct gggggcgcag aagggggcct gggccggggg 156720 atgttgtggg ccattgattc tgtcagccag gtcaggagtc tgaggtggtt catccaggat 156780 gacttggggg cagggctttg gccctgagca tctccccagg aacaaaaagg gcctcctgct 156840 ttctccccag ctgtcctttc actttctctc tcctcccccc gcctcccctc tctggggctc 156900 cctccgcctg tccccctcac cccacgacca tggacgtctc cccccgctgc agcctgctgc 156960 cacacagcct ggctttccag gcttccgcag ggtgtggccc cactgtaccc ctagagactc 157020 caaaacctga gagtggcttg gaggaccaga gaccccagca cggtgaacca tcccattagg 157080 cccagggcga gactggggtc aaggcccagc ttgtggattt gggcacccct gtgaccttgg 157140 gcagtgaatt cagccttcta agcctcagtt tccccatctg taaggtagga gaataacagt 157200 tgttatccaa gaggtcctat gaggagtgaa cgagtgatta cctgtgaggt ccttagtgcc 157260 tgccagaggg gcagcgctcc gggagggcga cgtgccctag ttactcttac tgctgtggtt 157320 attgttattt tatctggatg ccatctaccc ccttctcagg gccacctgag gccccctctt 157380 tttttttttt tgagttggaa ggttttatta gactaggaga tttgtgggag gtatgagcac 157440 tgggccaagg tggcacgggc catgcttaag gcaccctgtt gagtgtggtg accaccagtg 157500 aagccgctgg cgtggacgaa catgcagcca gagatcccac tgacgagggc gcctcttgaa 157560 cggtgcgtgc aggcacagcc acagtgtgct atgggttggg agcagggact gggcccagga 157620 gagctgagtt tgaacgtagg ctctgccacc tactagctgt gtggccttgg ggaagtgacc 157680 tgtgctctct gtgcctcagt ttccccatct gtgaaatggg gacaataatg gaacccactt 157740 caaagggctg ttatgggaat acactgggtg gctgcctgca gagtgctggg aatgcggcct 157800 agtatgcccc agacactctg ctagtgagag ctgtgatggt gctggtggtg gcacactcac 157860 gattgattga ttcattcatt cattcatcca ttcattcaaa gaggcatccc agaaggatgg 157920 tgcagagcag ggctttggag ctggtggctt tgtaccccag ctctgccgct tagtgactgg 157980 gtccaaggat actgggcttc acctctccgt gcttcagttt ccacctctgt aaaatgggga 158040 taagaatggg acccagtcgt agggctgttg aagaacaagt gtgtttcttt ttgtaaaggg 158100 tggtgcctgg tccttggtca gccctcaata agcattcagt attatcctca ctgtccattc 158160 agcagcccca tattcagcgc ctgctgtatc ccagggaagc aatggcagct gccctgaggg 158220 cagagacatg gatggggttt tcctgctggg ctgtggagct aacacttcgt tagtggaccg 158280 tggagggagt gggggctgca ttgaaggatt ctgagctgag acacagcccc catccagggc 158340 tggactcaaa gtgggtcgtc ctagtgtcga tgaaagtgat tctgatccga atgacacagt 158400 caaagctgat aaagaaggtg gcccttctgt cccctgacgc tgaagactct ggaggcgtgg 158460 acaggagggg accccgagat ccaggttggg acctggatga gaatgagtga tttgggagtg 158520 tggggttggt tctcgctcct ggccgacctt gaaggagcac cctcatatcg cgggctgcag 158580 agaaagcgga gcagatgcag ggacccacta caggaagtgg ggctcaggcc aggccatccg 158640 tcttgacagt agccgttctt ggtgtagtgg tgagctcccc atcgctgcag taagcaagca 158700 ggtctcacca ggagaggtgc cgctgaacct ggtgacctcc acctcctgcc cctcccctgt 158760 gcctttcagt cccagggagg agggcatatc ccagtgaatc ctaacgcagt atcagccacc 158820 tctggctgct ggcccagccc tgtctggagt acaggaagac atgtcaccct tggccagaga 158880 aggaaggagt ggggaagcag agggtcagtg ggtgtcccct cccgccttgc actaggtctg 158940 gcccgagtgt ggccgcaggc gacgtcagca ggaagcagga tccggcggcc gggcgggcgg 159000 ggcatgtccc ggagttatgt aacacttggc atcagtgtct tctacgaggt ttccctcccc 159060 ctccttatgg ccgaaggtta cccttttctc ccatctgtga attcaggccc ctggggctcg 159120 gcttccacgt tcctcagtct ctgtccgcct cagccttggc ccagccccgc cttgttttct 159180 gctgttaatc tcttctacct gaggctgcac aggcctgcag agagatggtc cagccacgaa 159240 atgtttgaag ctggcctgca ttcaaatctg agctcctcaa ctcatgagct gtgtggtctt 159300 gggcaagtgt ctttgcctct ctgagccatt gtcactgtct atcaggttca ttcatctaaa 159360 gacatagtta cagagcgtct gttctgtgct agacactgtt ccaggtatgg tgggaataca 159420 gcagagaaca aagatcccag cccttgagga gctggtgcga gagacaggtt cacacactca 159480 atttcagaat ggagtctgaa gatgctatga gaagaatgta gtagaaagtg attgatggtg 159540 ggggtgggag ggatgagcta atgatggagt gatcagggaa gacctctctg atgtctgagc 159600 taaggcccga aggaggtgag gaagtgagtt atgcagatat ctaggggaag ggtgtccagg 159660 caggggaaca gccagtgtag aggccctgtg gctggggcag cgagcaggga gggcagtgtg 159720 tttgtagcac agtctctgag gaggggagag gggagagcag cttggagagg caggcagggt 159780 ccagggctgg atcacacagg gccatatgga tagggggagg acttggggat tgtatccagg 159840 tgttggagag tttgaagcag ggggtggcat gcgctgattt gcagagcagc tgtgcaggtc 159900 cagtaaatta ataccagaaa ccgcttggcg catagtaggt gcttaataaa cgtcaggcat 159960 aatgattaat gccatcacta gcatctccta ttctacacac acctcctgat cccacagtgc 160020 cggaccatgt gtgtaaggat taactgtaac tcctgggact ctctctgaga cccagctttg 160080 tggggattca gggtgttggc accatccccg tccactgcct cagagacccc acgccgcccc 160140 ccgcagagac accttgcact ccaggatgct gggcgccacc accaggccga caggagaccc 160200 ctgttccctg cgagactctg agcatctccc atgtcccagc caccgcccgg gcagctcagg 160260 gcacccagcc ctgagtcttt cctgagcctc tgtctgccaa aaatagattc gggaagcagg 160320 gggagccctc ggccgcagcc gcagaaccca catgccacca ctttctcagg ccgccacagg 160380 ctcgaactct cctgggagag gctcaggatt cggggcaggg ctgggactgg gcccaggacg 160440 tgtgcggggt tgcagagctg ggcatccctg tgggccctgt gggcactggc aggggcaggg 160500 ctgtggccct ctggccgact gttggtgtcg gaaactgtga ctaacggacg agcagtcgtt 160560 tcccttttcc tccctgcgtt ccaaggggct gtgctcagag gaaccctgtt tgctcaggaa 160620 gaaggcagga caggaagtga tcccactccc tgcctgtggc tggggcttgg agcccgagac 160680 cccctctcct cccctccatg aggcccagct ccagcctggc cacggtgaag ggctggggtg 160740 ggcggggccc acctggcatt tgcccgagag caggctgtgt ggtctggacg tcagcagctt 160800 tttcttggaa tccgggtgca ccagcgcaga gggatgtgtg attccccctg gctgccgcaa 160860 ggaagtacca cagaccggtg gcttcaaaca acagagatgt attctcttcc aattctggag 160920 gctagacgtc tggaaccaaa gcgtccacag ggctgtgctc acattcaagg ctgcagggga 160980 gcctcttccg tcttccagcg actgctggca gttcgtgaca ttctttggct tgtagctgca 161040 tctctccaca tgtgcctcca ctgccacagg gccttcgtgt ccctgaatcc gtgtttccct 161100 tttcttccaa ggctgtcagt cctgttggat ttagggccca ccccactcca gtgtggcatc 161160 atcttaacta atgacatatg caggatcccg tttctaaata aggtctgagg ttccgggttg 161220 atgtgaactt tgagggacac cattcaaccc agtacagggc tcttggctga gagctgcggg 161280 cacctccagg tgtggcggag ggcccacctc tttctcagca accccagagg gatcaggctg 161340 ccgccccccc gtcacaccag gctgtggtgg gcacccccca gtgtctttcc agtccccctg 161400 ggagtcccca gtcacttcga gatgctgcct ccacgatgcc cctgctctct gctgtctatg 161460 cgttcaagcc cacgaaggct ggcctttcac agttgctcag caagtcagtc aacaaacgct 161520 ttctgagcct ctgcctggct cagcgtgggg acaaagagac acccacccca gtgagctacc 161580 aagacgagtg gtttgatgat ggtgcctaag ctgggggaag aagagtgggc tctgtgtgtg 161640 aggagctggg gttcccagga gcagggtgcg gtgcggggaa agtggaggcc cgacgatgag 161700 ggcttctttc cattcctgga cacacccggc atgttcccca cactggggcc tttgcacctg 161760 tgactccccg cacctgccac tctcgtccag agcctggcct ggcccattcc ctccgccgtc 161820 aaatcttggc tcaaatgtca cttccttgca gaagctcttc cagactgttc tgtccagagg 161880 agcccctgcc ttgtgctcct tgtcccatcc tgtttcaccc acgcgaccct ctgatcctct 161940 gagtgctgct tctgtgtgag gagcacgttg ccagtctccc cagcggcagg gcagcctcca 162000 agggcaggac cttgtctacc ccgtgccttg tgtccccaca gccctggtat gcagagctgg 162060 gcacacagta ggtgttctgt aaaggttcag ggaatgaaac gcgagcttcc caggctggcc 162120 tgttccccca gggacaggtg agacttgcat agcaaggaaa agcttcctgt gttcattcac 162180 tccacgtgtg ccgatgaagc tgacagggtg tccccaggag gcgtggtcac tcgctctgac 162240 taggagactc ctgggcaatg tcaggcaggt tctctcgtgc tcaggaagga tgtcagggtg 162300 gctgaggggc cagcctgtac ccagagtgta tctggggctc aatggaagaa taaagccccc 162360 ggtaaaaata aaccctggca cgcttggctg ccgaggtggg gtgtgagggg gacggtcacc 162420 ctcattgcta catggccggg atcactgccc tttgcacctg cggcgaggcc ccaggcatgg 162480 ggagtccccg agctgacagc ccaggcccca gtcctgatct gctgcttccc tgtgccccag 162540 gagaaggaga ggaacgcgcg gaggaagaag aagaaagcgc cggcggcggc cagcgaggag 162600 gctgcattcc cgcccgtggt ggaggatgag gagatggagg cgtcgggcgt gagcggaaat 162660 gaggaggaga tggtggagga ggctgaaggt gagggctggc gcggcttgga ggtggctggc 162720 agctgtgggt ccgagctctg agggagggca tagcgggaac tgatcccggc agcctcctct 162780 cccctgagtc atctgggtcc tccttagaag gggcctcgac tccctggaag gtgcgggcct 162840 gacttgccag aaactcacca gtaatgggca caaggatgaa ggccataaca atactgagaa 162900 taatcagctt ctctgggagc cccaagcctc gctcagctct tctgatgccc atgagtccag 162960 tcttatgctt gggtgaccag acgtccaggc cagccctgtg ggtgcctgct gtctttcacc 163020 ccatccgatg tcacagttta gaaaaaaatt tactttggaa aagttttttt ttgttttttt 163080 ttttttcaga cggagtcttg ctctgtcgcc caggctggag tgcagtgacg tgatcacggc 163140 ccagtgtaac ctctgcctct cgggttcaag caattctcct gcctcagcct cctgagtagc 163200 tgggattaga ggtgcccgcc gccacacccg gctaattttt gtatttttag cagagatggg 163260 gtttcgccat gttggtcagg ctggtctcaa actcctgacc tcaggtgatc tgcccacctt 163320 ggcctcccaa agtgctggaa ttacaggtgt gagtcaccac gtcaggcccg aaaattgttt 163380 tttgaccaga actcttttac aaggtaacca gcataaatag aacctatctg tcagtcggta 163440 aatattgtac aagttatata gttattttca gtgtctcctt ttattcccaa gtgtccctat 163500 ttgagtgata aataattcag tccccttctt tggtgtcccc gttttctcta tggggaaacc 163560 gaggctcagg cacttaaagg cctgggccca ggcgccccag gtaccacgga gtgtgttgtt 163620 tgcaccagct gtagactaga caaatgcccc accaggtgag tgctgctgaa gagagggcgt 163680 aaagccatcg tgtgcatggt gctggtgggt ccccccgagt cccctcaaat gcaggactgt 163740 gaccacatga gctgtgtgtt gtccagggct ccggataaca cacggctcaa ctttgttatc 163800 agtgtgtata gacccgggaa ctgaacacgg gctgccgaca cctggccccg cactctcggt 163860 cacgagtgca tccaccttcg acccccaccc tgtgcctctt tttccctgtc aaaggggaag 163920 ctgggggtct agactgctcc ccctgtggcg tgaccgaagg cccctggagg acctcagccc 163980 ttctctgctg agtgtccctg actctccttt ctgactctct gaaggagaaa caagcagccc 164040 ggcggagccc aagtccttgg tgaattcaac cctccttcct cctgccccgt ctggggtcct 164100 tcttgttgtt cctgttgtcc ctccctctct gcctttgaac gccctggctt ctccctggca 164160 gaaggtgcaa gtcacctcct ggttccataa gcccagcctg cagataaatc caggctcctc 164220 cagcccgcag ggtttcacca gcccgaatcc ccgcttcccg ctggaaatgg gcaactgggc 164280 ccttgggtga ctcatctcaa gttgggggcg ggtcagggac actgagtctg gcctccccac 164340 cagctttggg tctctctgac ccaagttgac cagaagcctg gctagtgtct gatggaagga 164400 aggcctgggc cacgagtccc ttgggtcgtc ccattttggg tcctgggtct gtagccagga 164460 gaagaccccg ggagcagaaa cccagtcccc tctgtaaata tccctccagt gtctgaatgg 164520 gcgggatgca ggcttggtgg gagcatttca ggaagccaag ccatggccac acattaaaac 164580 cggagcagac gccacccagg actgtgtggc aacgaccccc gcatcgcttg cagagcttac 164640 gtagccccgt agggacgggg aggggcatgc tctgctgggt gggggaggag ggagggctga 164700 ggtggctgga gctgaggctt ctgtgacagt ggtggtcttc cgtggctgct ctgagagatc 164760 agggacggca ggtgagaggc cctgattaag cctcctggtg cccagggtgt tagcccatct 164820 taaggacgag gagcccaggg gagaggagaa cccctcccat ggggtgtccc agcacatagc 164880 cggtaggctc ggggtctgcc ggcccagcca gcgcacgctg cgtgacctgt ctcttgtgct 164940 caggatgggg aggtgaggca ggtgctgggt tggagcctga ggttgccctg cctgaatctc 165000 cccggagacc cagccagccc cagcggcact gcaggcccct ccccgggggc agtggaaagc 165060 gtcttgttgc atctgggctg gaaatacacc agcgcggggc tgggagtgat accctggccc 165120 agtggtttct ccagtaataa taatagtatc ctcatagtga atgaagccat gctgttctcc 165180 gcatttgaca gatggggaga ctgaggcata gcggggttat ccaaggcgca tttggtgacc 165240 ggggttcaaa cccaggcagc ccggtactgg ggacctccag gcagaaagga aaggaggcca 165300 tctggtggtg tgtttctatt ttttattttt ggtggttttt tggtcactct tgttaagcac 165360 ctactgtgtg tcagatgctg cacaaagcac ttcacctgga ttctagggca gcggtggcag 165420 agtgttccct gggatttgtt agaagtgctg attcttgggc cccagtccac acgtactgaa 165480 tcagaaacct cggggcatag tgcagccacc tgcactgtca caagcccttg gagtgcttct 165540 catgcaggct cctgccccag acccccttga taactgtgag accgagaagt taactgccca 165600 ttttgtagat gaacaaactg agacccagaa gtttcatccc tggtcctggg gccctcagcg 165660 ttggcctccc aacgtcctgt actctgactg tggaaggaag ggaatgacat tgctgaagtc 165720 accaggcaga ggaaggccag gggttaagga cacaggaagc tgggctcagt gctctcccct 165780 ccacagcgtg gccttgggca agctgattaa cctgtctgcc tccatttcct catctgcaca 165840 tgagagttgg tggtcccagt cttagaggtc ttaaaggagt cgtgtgtgaa gaactcggca 165900 cggagcctgg cctgtatgca gccagcgttg ctgctgttgc tattgtttct aaaaagggtg 165960 gcctctgctc tggggcctga agggaggtga gaagcaggag agactggagg gttggtgggg 166020 gggcaatgaa ggctgaagag gccccagcag ccccaaaagc ctctccctgc aaccttgccc 166080 atccctgagg tcaacacctc ccactccagg catcctggga gcctggttcc accaggaggc 166140 tgatgactta gggcaaggac acccagagtg gctgaagctc acttttcacc ctgaacaacc 166200 ccattattgg ctggccttga acaggccatt ggaccagcct gctcagggct attgcaggtc 166260 acctgtggcc gctggccaga gcccagaggg agagggctca tcggtccatg gagaagggca 166320 gtcggggcag gagagcgagc agcagcgagg cctcactgct gtgcactggg cttcaggccc 166380 ctcttggcca cgttgcctcc tccctcccct cccactactt ggtgctgcct cacttctaac 166440 tcttctctga cttccttcca gccttacatg cctctgggaa tgaggtgccc agaggggaat 166500 gcagtggccc aggtacgaat gtggccggct ggcctggggg gtagggccgg gccggggcgg 166560 gcatcccaag gtccccggtc ctccacaagg aaccccgctt ctgagcacat gcctctttct 166620 gtgagcgcca ccgtttgtgc tccgcggcct ctgggcttcc ttcccagcac agtggctgtt 166680 ccccatgctg gtcccgggct cactccagca gaccagtttc ccgtctccac tgctttgctg 166740 attttcactg gtacgcttgg gtctccgacc gggtttgatt tccctgatag caaatgcagg 166800 ggttttcaag tatccccatt ttacagaaaa tgggagacat tgagactcaa agaagagccg 166860 ggtgtgggtt tgggggctag agagccagga atgcggctgg gctctccttg ccatccttgg 166920 gtgcgtgctt tcatcctgcc actccgccag cacagatcgc gctcctgctg tgtaaaaccc 166980 atgctgaggc cgttggtgtg ggctgtgccc ggggcccctg cacacgcact ggcctcgttg 167040 tccaccgtgc ccggggcccc tgcgcacgca ctggcctcat gattgtccac cgtgcccagg 167100 gcccctgcac acgcactggc ctcatgattg tccaccgtgc ccagggcccc tgcacacgca 167160 ctggcctcat gattgtccac tgtgcccggg gcccctgcgc acgcactggc ctcatgattg 167220 tccactgtgc ccggggcccc tgcgcacgca ctggcctcat gattgtccac tgtgcccggg 167280 gcccctgcgc acgcactggc ctcactgccc actgtgcccg gggcccctgc gcacgcactg 167340 gcctcactgc ccactgtgcc cggggcccct gcgcacgcac tggcctcact gtccactgtg 167400 cccggggccc ctgcgcacgc actggcctca ctgtccactg tgcccggggc ccctgcgcac 167460 gcactggcct cactgcccac tgtgcccggg gcccctgcgc acgcactggc ctcgtgattg 167520 tccactgtgc ccggggcccc tgcacacgca ctggcctcat gattgtccac tgtgcccggg 167580 gcccctgcac acgcactggc ctcatgattg tccactgtgc ccgggcccct gcacacgcac 167640 tggcctcatg attgtccact gtgcccgggt cccctgcaca cgcactggcc tcattgtcca 167700 ctgtgcccgg gtcccctgta ctcacactga gcgcattcta cactgtcatg tgacgatgat 167760 ggtggcgatg gtggtgcagc agcaggcagt caccaggcag ttgcccttgc cctcacaatt 167820 gccagcttct ccgccctgtg agatgggaac tattgttctc ccgttctgca gatgggaaaa 167880 ctgaggccca agaggtaacc tgagtttccc gtggcacgca gccagtgcgg ggcagagccg 167940 gggttagagc tcagatgaga acatggagac ccccaggacg aaggcctttg cccacggcca 168000 ccctcaggct ggctccatct gtcgggggtg ctgaccacca ggaggtcctg gggttgggaa 168060 ttaaccaggt tatgccagca gggtcagtct gggagaaagg cggccaggcg agggcagcag 168120 ctgtgggtag gggcctggtc aggggctttg tctcaggggt ggggctctag gcagcagccc 168180 aggtgtgtag gagcctcggg gctgttttgg catcaggcga cagagcggcc tcatccggag 168240 ggtcagggcc atgcatctct tctggaggcc ccgccagacc ctgctcatcc cctcttcctt 168300 ctcgccctgc acagccactg tcaacaacag ctcagacacc gagagcatcc cctctcctca 168360 cactgaggcc gccaaggaca cagggcagaa tgggcccaag cccccagcca ccctgggcgc 168420 cgacgggcca cccccagggc cacccacccc accaccggag gacatcccgg cccccactga 168480 gcccaccccg gcctctgaag ccaccggagc ccctacgccc ccaccagcac ccccatcgcc 168540 ctctgcacct cctcctgtgg tccccaagga ggagaaggag gaggagaccg cagcagcgcc 168600 cccagtggag gagggggagg agcagaagcc ccccgcggct gaggagctgg cagtggacac 168660 agggaaggcc gaggagcccg tcaagagcga gtgcacggag gaagccgagg aggggccggc 168720 caagggcaag gacgcggagg ccgctgaggc cacggccgag ggggcgctca aggcagagaa 168780 gaaggagggc gggagcggca gggccaccac agccaagagc tcgggcgccc cccaggacag 168840 cgactccagt gctacctgca gtgcagacga ggtggatgag gccgagggcg gcgacaagaa 168900 ccggtgagtg ggcgccaggc agccctaacc ttggcttttg tctgcagaca ctgagcagcg 168960 actacctact tagacagccg cacccagtct ggctctgcct gctttggggg agcccgaggt 169020 gtggttaggg aggcagactt ggagtagagt ccaggaatga gagatgcagg ccaggaaggg 169080 gcggaggtgt ggccgggagg acctccccag gaggtgacat ccaagctgag acccggacag 169140 aggaggcagc cctgggcagc gctagggaga gagtgtgcca ggcagcctgc tcgcttccta 169200 gggccgccct cacaaggtag ttcgagccag gtggctttta acaaatacag tcctggaggc 169260 caggagcctg ggggcaccat gcaggccgag acgcagcctc cgagcctctg ggcagatcca 169320 tcccgcctct tccagctcct ggccgctgct ggcggtcgtg attgctggca tgccactccg 169380 tctttggctc tgctgtcaca tgaccttcgc cctgtgcatc tctgtgtcca cactttcttc 169440 ttctgaggac accaggcatt ggatgggcag ctgtcctaat ctagtgcagc ttcatcttaa 169500 cttgattata tcagcaaaca gtctatttcc aaataaggtc acattcacag agaccctggg 169560 ttaggacttg aatgtacctt ctctgggggg acacagttct accctcagcg tggtgggaac 169620 agcaagtgcg aaggcccgag gtgggaatga gcttggtgga ttcaggtgcc aaagggtggc 169680 tcagggaggg ggcagcctgg caggacgggg ggcagctctc acgggggtgg gggcactgag 169740 tcacgccctg gcaggtgggg gctgcatttt gttctcaggg cagtgagaag gcctttacga 169800 gcctctccca agagagccag atgtgattta cccatgaaac catgtggggg atttgctggg 169860 agtgagaggc acagtcagga ggcagctgca agtgccctgg ggctggtgat ggagatgcga 169920 gcgtggtggc cgtggggttg gggaaaagcc acaggttcaa catgtttttg gtggctcatc 169980 tcccatcagc caagggtcca gggctcagga tcacaggtga tcaccttgga tcacaggtgc 170040 agaggttccc cttgcaaatt cctctccagc tggggtggcc tggaggaccc cagtgtcgtc 170100 ctgtttgggt gttgatgtct ctgaggtgtg ttctttcctt tctggcctct gtctttgctc 170160 ctggcctggg tgaccccaca tccctgagaa tgccaccttt tacccatttt cagcacagat 170220 gctttgggcc tcaaggcctc cagcccagaa ccaaagatgg ctacccaagt tagggccaat 170280 ctcggttggc agagggcaga cccgcggaga ctgcgtcctg ctcacatctg gatggctgga 170340 ggaattgttt tctggtgggg caggcaggcc attttatttc aactacagtg tggtctgttt 170400 tctcccctcc caagtccctt ggaatggtcc tgggcagagc aagcgaggga ggaaaatcag 170460 acccgcaggg tcatgcgggg cccttgtctc tgccctgggg ttcaccctgg gccatgttaa 170520 agggggaagt cctaggacat tccctaggaa ctgaggttca cccggatctc tataggttcc 170580 acaaaacaaa atctcagggt ccccaggaac cactgccaac aggaaccgcg cccatgcgtg 170640 tgagaagtgg acggcctgac cctgaccctg tgatgagcaa aggcctggcc tgcgggtttc 170700 tgagggcacc aaatccctga gcttcttgcc cgacagtccc agcttggaaa acagtgttca 170760 tggtgtggct gggtctgccc tggaggcagg cagccagggc cattgtgcct ggatagcggg 170820 gtcagggcag acggctcccc gccccgctcc tgctggctgt ggggacagag tcatagaaac 170880 acatgtttct gccttcgccg ggggaccgct gaggtcatgg ggcagcccca ttgataagct 170940 gcctcccaga gtctgtattt tgggtccatg tggctggccc cggactgggg agccggggga 171000 tcagcttgca tcctgtccgt ccccagaaca ctcaggctag gcctgaggcc ccgcagggca 171060 cttgcagcct cccgtcctct cccctgcagc cccgcccagg gccgtgtcct ccctccccga 171120 gctgggcctg gcgtacgtcc accccttgcc cagtgtccag cacacagccc ccgggtgcag 171180 gagtcctcgg ctgggagtca ggacacctgg tttgtcccgc cctgtgcgac taggcccagg 171240 cccccgccct tggggcctgc tttgccctct cagtgaacga ggctggactc tggccagcct 171300 gctgacctcg tcctggccgg cagcccgcca cccctccctc tgccggccac gactgcgcag 171360 ggccgggcgg acgctggagg acgcggacga gatgcgtcag agtaggccct ggcagccagg 171420 gcctcccggg aagggctggt gggacgggcg ggccccccag gcgacccctg ctcctggctg 171480 cccgcccagt atcatccctc ctgcctggca gccccagtgg gggagctctg tgttcctgga 171540 tggacgcaag atgactctca tctggccccc cgccccggtg actttgggag agagaaaatc 171600 acattctcct tcggcccgct ggcactttct tcgaggtggc tctgcctggg tgttttcttg 171660 gcagacgacc agagatagtg gcttcaattg caaaaccccg agcctgcctg ccttcccctc 171720 tcttactctt cagagaaggt gcctgggtgc ttttttggca gggcctggcc ttgggagtcc 171780 cctcccccaa gcctcagttt tctcatctgt aaggtgggcg tggatggctt attgcaagaa 171840 taactcagtt aatgacgggc cacagtgggc gctcagagat tagctgccct cctttggatc 171900 tgctttggga caccccctag aggtcacccc aagagggggc tggagtgcag ctccttcagc 171960 tgtccctctg gcattttgga agatcataac agcaatttca cctttgttac tttattctgc 172020 aagtgactga tggcaccagc atgcgccagg cgccgggggc gctggaaact gcacagacaa 172080 ggccctgact ccaggcactt acattctagt gagggcatgg agaaggaaac cattgtttac 172140 gggatgagtg ggtgatgggc agatggggca tggggagcag gggagagtgg gctggtcagg 172200 cagggagggc ctctggggag gtgacattgg agggcaatga gagccttagt gtgagggaaa 172260 gccagacccc ctgggaacca ccagtgcaaa ggccctgtgg ccgcatgagc gtatgtccag 172320 tggacagcag agaggcctat agcagggtgt agagtggagt gagcagccca gggcagagag 172380 ggcggagagg tcagagaggt gggcaggccc cacgggtgga agtgacgggt cagggtttta 172440 tcttggggcc ttggagaggc aagggatgcc tgttcacaaa ccagccctcc ctctccctcc 172500 tagccctagg atggtggcaa ggattgtccc agcttgatga ccatggggaa actgaggcaa 172560 gggctgggtg gagaggggat gtactgttgc aggcccagca tgttccgatg aatgtcccca 172620 ggcccttatt ccccctctcg tgccctgccc cccaaccggc cttcatgagt gggaaggaaa 172680 atgacagtga ggagaaggtg gcccgaccca ctcggcccca cgtgctggtc accagcatcc 172740 ccacgcccac ccacggacag cccttgaagc tttcgtctcc actctccaga ttgagaaacc 172800 gaggcacagt tggctaagtc acatggtcag agaggggatc cgagcctttg ctcgcaactg 172860 cagggctggg taggcagggt ggggcccctc ccagacacat actctgtgcc aggccctgag 172920 agtccccgcc ccacccaggc cgccagaaag gaaaatagaa gtggctgcct tccaagaaaa 172980 caaaggagag aggccggtcg cggtggctca tgcctgtaat cccagcactt tgggaagcca 173040 aggtgggtgg atcatttgag gtcaagagtt tgagaccagc ctgaccaaca tagtgaaagc 173100 ctgtctccgc taaaatacca aaaaattagc caggtatggt ggcgtgtgcc tgcaatccca 173160 gctactaggg agactgaggc aggaggatca cttgagccca ggaagcagag cttgcagtga 173220 gccaagattg tgccactgca ctccagcctg ggcaacagag caagactctg tctccaaaaa 173280 aataaataaa taaataaaat aaaacaaaga agggagagtg gagggtgggg agagccagcc 173340 aggagggctt ctggaggtgg cgctcctcca gcatggctac gggacaaggg gcggtcagat 173400 gggccctgag ctctgagcgt tttccacctt cctcctccac tattggtggc cgctccctct 173460 gggggcttag gactctcgtt cccctcgaga acttgaaccc agcccttgtg ctggctgctg 173520 ccttctttac ccatgagaga gctctggctg ggatcagaag acctcttgta aactataaag 173580 tggtacctcc atgaccacag tccccacttg ctctgggggc tcaagaaggg tttgggcctc 173640 tgtgtgtgcc ccccagaggg tacctgctga gagcttctgg gcagcagccc ctgcccccgc 173700 tcaccccctg ccaatctgac tgcccacacc ctactaggtg aggggccaca gggaaaccaa 173760 ggcacaggga gcactcaggc cccacataga aaacgcgagc tctcgggcag actgcatggg 173820 acagtggcac ctcatgtttt gtgtgtgtta taaagtcata tttttatctc tatagaatta 173880 tctttacaca tatacaaacg tttgcatttc aaccttaaaa tttatatttt atttttctat 173940 ttgtacacac atataaaaat attattttta ctgttcatag agaaaataca gctgatacgt 174000 cgaacccttt atggctagca tatagtatgg tcctcatttc attttgtaac cgttattaag 174060 atatcattca tataccatac atttcaccat tgaaagcgta tcatttaggc taggcacagt 174120 ggcacacacc tgcaatccta gctctttgag tggctaaagc aggaggatag cttgagccca 174180 ggagttcaag accagcttgg gcaacataga gaaaccttgg ctctaccaca aaaaagaaaa 174240 aaatgcaaaa atcagtcagg tacggtgatg tgtgccttta gcttcagcaa ttccggaggc 174300 tgaggtggga ggattgcgtg agcccagggg gtcaaggctg cagtgagatt acagcactgc 174360 actccagcct gagtgacata gcaagaccct gtctcaaaaa aaacgtgtat cattcagttc 174420 ttcttagtat attcagtgtt atactaagaa agaaacccta tgcccatcac tagtcacccc 174480 tatcctccct cctcccagcc ctggcaccca ctcatctcct ttctgtcccc gatggattgg 174540 cccgttctgg acttttcaca gaaacggaat ctacactaga ggccttctgc gactagcttg 174600 tttcacgcgc atcgtgtctt cagggtccac ccacgtcata gcccgtgtca gagcctcatg 174660 ccttttgatg gccatgtgtt ccatcgtgcg gacagggcac gctttgtctc ctcattcgtc 174720 tcttggtgga tgtcgggttg tctctgcctt ctggctgttg tgcgctgggc ggtgctgcag 174780 tggtgggcac gtgcaggttt ctgcatagac atttgctctc atttgcctgg tgtgtgccta 174840 ggagtggcag tgctgggttt agggcaatga gggctcaccg actgctttcc aaagtggctg 174900 cagcattctc ttttaaattt cagcttgcaa gtgcgagctg gttgaaacgg atggtggtag 174960 gtaaacctgt ggggagggac ataggggtgg cggcagttga agccgcaggt ggagaatgtt 175020 gggacaggtg ataccatctg tgtttggacc tgggtcaggg taccttgtct gtaccttgag 175080 gatggcgggg agagcacagc tgggcccagg tccagggagt gaggcatggc agtggccaaa 175140 ggagaggctt taggtggtcc tgggagatca agcagggtct ggacaggtgg agggagggga 175200 gggaggagag tgggctggcg gtgggggcgg tggaggtgca tgcagaagtc agggtgacct 175260 tcctcgtctg gcccccgtct gtgcgccatg ggcagcctaa gcaggcatca ccgagtctgt 175320 gtctgctctc cccgctcagc tgagcgtgtg gcagatgcag acagcaggct ggtacctgca 175380 gaacaggccg gtcacatgcc ggtggcccca tggtcctgct atggcagaga ttgaaggagg 175440 ggactgccgg caggggcctc agcaccctgg gcatcggccc tgctcatctg caggaaggag 175500 atgggtgcct ctgggcgcca ggcatccagc actggcagct ggggactggg gtggtgtgag 175560 ttgtgtccct gttgtcacag ctctcacctc gaggccagta ggctgtgact tatagtctgc 175620 ataggacgtc gtcactgtgg tcacagcaca gagtaggggc tgtgccgaca ggacctgcca 175680 gcttctggca cccagaagtt ttgccctctg gctgaattcc aggcccgtgg ctgctgccct 175740 cacgcctgcc atgtggtcat ttcactagct tggaagacct aggacagaga ctgggttctg 175800 cgtcgcctcc aaatacaccc aaatgcaggc cgggctgctt ccataccccc aaacgtaggc 175860 cgggccatct ccatacctgc aaacgcaggc caggccacct ccataccccc aaacataggc 175920 tgggccacct ccatacccgc agacgcaggc cgggccacct ccatacccgc aaacacggtc 175980 caggctgcct ccaaataccc ccaaactcag gccgggctgc ctccataccc ccaaatgcag 176040 gccgggctgc ctccatacat ccaaatgcag gctaggctgc tttgtgccta gcaaatgcag 176100 gttgcaggag ggagtcaaga actgggcagc cccgggcagc cacactgggc aggtgaaggg 176160 ttctcaggct ggagcagatc cagttcctgc ccttggagac ctcatgccaa gtggggagcc 176220 agatggggat tatggcaggt gctatacccg gtgctgggga cttagaaatc ctggaaggct 176280 tcctgaagga aacggcaccc accgaacagc ttgggagcca caccccaatg cacgctctgc 176340 caggcaccgt gtaccctgtg tcggcctctg gtcgcgcatc tcagtagcag acagaggaag 176400 ggactgcgac tgtggctaat gagtagacag tgggcaggcc ctacctgccc ctccacacaa 176460 agtctgtggc ctgggccctt gttatcatgt cctcgtcctt cgtggatagt gtgtgggaga 176520 gagtctagga agtgggtgca gctcccccac tcctgcctct ggtaaccgga gctcattcgg 176580 ctccatgccc actgtcttgc cctggcaccc gagcctctca gattcgagtg atgaggaatc 176640 tcttggtgaa tctcttcatt tctctgtccc tgaatcgggc tgattctttg gctttctggc 176700 agcttcggaa gggccacgtg tggtgtgggc cccaggtctg ggcttctctg ggattttcct 176760 tgcctggaga tgtctttggg gatgtttgat cccagcctgg gcctctagca ctgcccggct 176820 ggcctctagg ctggggtggg aggctggctt ggcccctgat ggggcctgca agaaccaggg 176880 gagtgagtga ggaggcactt gcccgcccac tcgtgcctcc cctcccctgg ccccaaatct 176940 tggtctgttt tcccaagaga aaccgttgac attatctggg tgagctgcac agtcgcctcg 177000 tgtctcaggg ccttagcctc gtccccaggg cttgagacag gagaggccat caaaaccggg 177060 cagccccccc accctgggag agtccggctg tgggccccca gctgatggtg ctcgtgtgcc 177120 cgcaggctgc tgtccccaag gcccagcctc ctcaccccga ctggcgaccc ccgggccaat 177180 gcctcacccc agaagccact ggacctgaag cagctgaagc agcgagcggc tgccatcccc 177240 cccatcgtga gtgcccaccc ccagagcccc acagagtcca ccctgacctt gactttccca 177300 ttcattgaga cagagaatcc cacgggcggg agcatgcacc tgcagcctag ctcatccgct 177360 tctgtttcct ggagaaatcc ccgtggagct gaggtgggaa cagctgggga agctggcagg 177420 cgtaccgggt ggggctccca gtgaaggcgg gaactggcgg cctaaggcct ccccccttcc 177480 accccgcagc acccttgaac ccccagatta gatactgggt catggggagg caggagcttc 177540 ccccacccac tcagctatag caacagcttg gccagggaag ggtggcctac cagttctgat 177600 cctggggccc tctgggaaca ccctcctgga aggttctctc agctgggtgc gtgggccctt 177660 ggaggtgcct tctccaggga ggtgagtctg gccttcccag ttgcaactgg gggctccggg 177720 ctaaaagacc ctgagctgac caggctggtg gtcccttggg actttgagtg atgggctcag 177780 ggcgtgtcag gctacacggc ccagtccccg aggcccacag aatcctgttg ctcagtcctg 177840 gcttccctga gacccagagg atttgggtcc acagaaggag ctggaggaga gagtcacagc 177900 aggctctagc ctcctgtcca ccaccaggct gctaggccag gctttttggg aggtgggctc 177960 cccctgtcca tcaccaggca gctgggctag gctttctggg gaggtgggtt ccccctgttc 178020 actaccaggc agctggacca ggctttttag gaggtgaact ccccctgtcc atcaccaggc 178080 agctgggcca ggttctggga ggtgggtccc cctgttcacc accaggcagc tgggccagac 178140 tttttaggag gtgagctccc cctgtgcacc accaggcagc tgggccaggc tttttgggag 178200 gtgggctccc cctgtccatc accaggcagc tgggccaggt tctgggaggt gggtccccct 178260 gttcaccacc aggcagctgg gccaggcttt ttgggaggtg ggctccccct gtccatcacc 178320 aggcagctgg gctaggctgt ctggggaggt gggttccccc tgttcaccac cgggcagctg 178380 gggcaggctt tctggggagg tgagctcccc ctgttcacca ccgggcagct gggccaggct 178440 ttctgggagg tgggcttccc catgtgctct gtgctaagac ctccctttct tgccgcacct 178500 gggaccttga gcatgtcgct ggctttcccg ggccttggtt tccaggctgg tcgcgtgcat 178560 gtctctccct gaccctgtca ctttcagaca ccctctgtga atgctcactt ctgcctgctt 178620 ccctcagcag gtcaccaaag tccatgagcc cccccgggag gacgcagctc ccaccaagcc 178680 agctccccca gccccaccgc caccgcaaaa cctgcagccg gagagcgacg cccctcagca 178740 gcctggcagc agcccccggg gcaagagcag gagcccggca ccccccgccg acaaggaggg 178800 tgagtgcaca ccagtggctg agtggggctg gggcagcagg ggactgacgg gcaagggatg 178860 tttgtgtgtc tagagcagct gctgcaaacc ccatggccac agtggcaggg aaagcaaagt 178920 aaacgaatgg aacagttgag cagggggagg cagttgggaa tggtagggac tgcggcaaat 178980 tggagaactc ttgttttctc taaagtgggc acgtattggc cttggccaag agtcaccccg 179040 tggcaaatca ggcctggggt ggttcttcca gcaaagccag aaatccatct tatgtgaaat 179100 ccccctggtc cctggtttct caacactggc aacttctcaa aattttcaaa agcattgtga 179160 acacgcaaaa acatgtctac agcccagcct ctgattcggt gtgaatcagt ccacgcagga 179220 gcttctggaa tcacagatgg ggcccagcac ccggctggca gcagctctgg ggcctgggca 179280 ggaagggctg ccctccccag ctggcatcct gaccttgctc caggcccagg tctctgggtt 179340 caccaggagc cagggttggg ggtgactccc gagccgctgt gtcacaggga ctgccccggg 179400 cacacctcac tgtcatcacg tgaagctcaa ggtcaggaga caggcgggcg tgattgcttg 179460 ttctctggat cttcaatctc tgccccactt cccactaggc ccaagaaatt ctgaacctgt 179520 gtccccaaag aggcatcttc tccaggtcag cctggcacgc agcaggtgct gttgtgcctt 179580 gcaggtgttg ggggctgctt ccccagaggt tccccaccct gggctagccc cggcgcttgc 179640 tggcaggctg ctccaaaggt ctgagggcag caggacacca ggccgacctc ctgaccagca 179700 cagcccaggg acaaatccgg gtgactggag ctaccatcag ctgtcccctc cccgctgcct 179760 tgggtgtgac atcccccttc tctttttttt tttttttttt ttgtttgaga cggagtgtca 179820 ctctcgccag gttggagtgc agtggcacaa tctccgctca ctgcaacctc tgcctccggg 179880 gtccaccgag gctgctgggt caggacattt gttgaaaacc caaggcccca ggcaccatgc 179940 tggcagagcg gggattaggt agggagaaga ggaagtctct gctctgggga gctgctgttg 180000 ttttgagtga ggaggatgtt aaaccaggga acacgtaacg aagcaagatg gttttagagt 180060 cgttcatcca ccatgagaaa caaaacgggt tgagtgaaga gcggctccgg gaaggaccct 180120 gtggagtggg aagcagcccc gcagtgggag ctctctgggt gggcattgcg ggcagaggga 180180 acagcacagg gaaaggccct ggtgtggaaa cacgctcggg gtgtgtgagg agtcgccggg 180240 ggtggttgtg gccagggaag ggtgggcggg tggacagtga gggaagtggg gaccggattg 180300 tgtggggcct ctcaggccac agcgggcagt ggattttgtc tcaggtgtgg caggggctgc 180360 tggagggatt tgaagtgagc gtgtgttgcg gaaggggaag gaggtgcttg ttatctgatt 180420 tgtatcttgg aaagctctgt ctggccgttg ttgagtcaag ggcagcagcg ggaggtcaca 180480 gcgcagctct tggcaggcga cagaggctgc ctgaaccgca caggtggccg tggaggtgga 180540 aggaagggcg catcgggagt ttgttttgga ggcaaagcca gtggggcgtt gaacccggtg 180600 tggggatgac gccagggatg tctcgctgga actgggatgc cccatgacca gggctgggct 180660 acctggggcc agggtacagt gtgcggccca gggtgtggct ctgggagacg ttgcaggttt 180720 ggggcgccag cccgggaagg agctgtgtat ccatgtcagg ggccccagca gctttggcca 180780 gcgtcagatc tgatcagggc tggaactgca cggtgccagc caggtcctgc tgagccaggt 180840 cgcaggcccc tgtcctggga gaaagggagc caccggccag cagttcccgc ggctggcact 180900 cagcccgttg gtgtggccag ggcctgtgcc gtttcctggc ctcattcccc gtggggacgg 180960 tgcacctggc gttaggccct gcatgccttt cttgcacagc ctggcttgca gctcagctcc 181020 cgcagggaca cacatgaact tgacacccag cgctacctct ctggtctctc aggaagccag 181080 cctattctgc ccctggctcc cacacagagc ggctcagcca agcaggtccc tcggggcccc 181140 ctgggcccaa ctggaggaac aggttgtctc tccaggctct cggccgcccg cccagcctgg 181200 cctagcccca gtttgccttc cagcatcgaa cagctcccct cctctctctc ccaactctct 181260 ggaactgggc tggaggaagc accagaggct tacagggctg ggtagccaga ggggccaggt 181320 ccagggcgtt tgcaggatct ccagatgtga ggcaggccct gtacaggtgc ctccactggg 181380 gactggttaa gaatgagaat tcccctgcat ctgtgccccc tgcctcctgt gggctgccca 181440 cctcgccagg gcacaagtcc aggggaaaca gtcttcaagg agagaattgg gggcaatttg 181500 gtacataggc cttcttgccc acctgctctg ctcacagcag gcatcattaa ttgatcttag 181560 cactctcctc cgctgtcaca ccctgatggg ccctcagaac ctcctttgtt catctggagg 181620 cggcgtgata gatgacacct gcctgccatt cctgtcccag aacccagagg gctccgtcat 181680 tcccaagttg tgtctctgct caacttcttg gccggttatc tctccatagg attggtcctc 181740 agggagaggt tcagagctga ggacagattt cagcaaaggg cgagaggcca gcaggaagat 181800 gccatgaagc caggcctgag ccccggggcc ccgctgagtt tacaggatct ccccaggcct 181860 gaaatctagg acccatcatt gcttctctgc cgcaggccat gtggcatagc agtctggatt 181920 aaggccatgg tctgcagccc cagtgcctgg gttcgaagcc gctatctgcc acttgctagc 181980 tggggccttt gaccaggtgg cttaacctct cggcttccat tttcccgtct gtgaaatggg 182040 gacagtcagt cagttccttg tagggtgctg tgagaataaa tgagtgaaca cgcttacatt 182100 gctgtcagcc gtggagccct gagagagcat gacctctcgg taatgccctt tgcacactcc 182160 gcctggtaag tagccctgcc tgagcttggc ttctcagcca gccagcgcac aaccgctgct 182220 tgcactggct cagtgggctt ctgatcctga ctcggctaag tatttgctgg tgaactcaga 182280 tgagcccatt ggtgtgtctg tacctcagtt tcccctctgt aaaatgtgtc tggcagcagt 182340 ctctgtgtga gcttaaccgg aggctcatgg aggccgtggg atgctgagca cagtgcctgt 182400 gctgagtacc actcagcaaa ctgaggctga cgctgtggtt gttacttgga gggtctgggc 182460 ttataacccc ccactgcccg ccacaacaca cacacacagg cgcacacaca tccatgcact 182520 cgcacacaca tgcacgtgca cgtgcacaca catcacaggt tacctccttc aacattgtgt 182580 acaggcacac acacatccat gcactcacac acacgcacat acacgtgcac gtgcacatac 182640 acacatcaca ggttacgtcc ttcaacattg tgtacaggca catacacaca tccatgcact 182700 cacacacaca tgcacatgca cgcgcacaca catcacaggt tatctccttc aacattgtgt 182760 acaggcacac acacacatcc atgcacacac acacatccat gcactcacac gcacgcacgt 182820 gcgcgcgcgc acacacacat cacaggttac ctccttcaac attgtgtaca ggcacacaca 182880 catccatgca ctcacacaca catgcacgca cgtgtgcaca cacacacacc acaggttacc 182940 tccttcaaca ttgtgtacag gtgcacacac acatccatgc actcacacac acatgcacgc 183000 acgtgcgcac gcacacacac atatcacagg ttacctcctt caacattgtg tacaggcgca 183060 cacacacatc catgcactca cacacacatg cacatacacg tgcacgcgcg tgcgcgcaca 183120 cacacacaca catcacaggt tacctccttc aacattgtgt agagcacagg ccagcaagct 183180 tttcctgcaa agagccggag agtgaacatt ttaggctttg tgggccagac aatctctgtt 183240 gcaaggattc agctctgcca tagacaatac ataaatgcac agatgtggcc acgctccagt 183300 aaaagcgtat tcacaaagtc agacggcggg gccaggcgtg ggggctcacg cctgtaattc 183360 cagcactctg gaggccaagg tgggaggatc tcttgagccc agtagttcaa gaccagcctg 183420 ggcacacata acaagacctc atctctacaa aaacaaaata taaactagcc aagcatggtg 183480 tggtgacacg tgcttgtagt cccagctact tgggagcctg aagtgggaag atcccttgaa 183540 cccaagagtt caagacaagc ctggggcaac atagcaagac cccatctcta caaaagtaaa 183600 acaaattagc caggcatggt gcggtggtgg gcgcctgtat tcccagctac ttgagaggct 183660 gaggtgggag aatcacttga gcccagaggt gaaggctgct gtaagccgtg acagcaccac 183720 tgcaccccag cctgagtgac agaaggagac cctgtctcaa aaaaattagg gggcagacag 183780 accctctgag ataccatttg ccacctcctg gcttagaggc ctgtccaggg accttggctt 183840 gctgggcttg gttgagtgct tgtggggttg caaagccaga gggtcccgtt ctcgtcctca 183900 gcggcagctg agagccccca gctcagacct tgagatcccc tcccctgctg agcagaatac 183960 catggggtta cagagcagcg cccaggcagg cagacttggg gggcttcccg gaggagccca 184020 ggccgtcaca ggccaccact actgtgggtg caggaaggcc atttgtgtag ggtcagccag 184080 ggctcccgag gtctgactgc cccacctcct gccctcagca gagaagcctg tgttcttccc 184140 agccttcgca gccgaggccc agaagctgcc tggggacccc ccttgctgga cttccggcct 184200 gcccttcccc gtgccccccc gtgaggtgat caaggcctcc ccgcatgccc cggacccctc 184260 agccttctcc tacgctccac ctggtaagta gctccgcccg agcttgggct tcttcagcca 184320 gtgcacaatc gctgtttgca ctgtttgcac tggctcagag ctgcacacag aagcatctta 184380 aagccttatg ggacctggct ggaggaacag cctggtcagt ggagggaaag ggggagatct 184440 tttaagaaag ctgccccagg gttgagatgg aagccactgg caagagggag ccacagcagg 184500 tgcttgagct ggtgaggggc aggcttagag tgggagctat gttttccgtt gacggcttag 184560 agctagagaa tgggcagatg gtagaagagc ctggggaggg agcagaggcg ctaccttggt 184620 tcacagactc tgtgaggctg catttcggcc ctgttctagg tcctgcagtc ctgctgggcc 184680 tcaccagctg taaagcagca cagccggggg ctggtacaga ctgctgttgg taaaggctgg 184740 tcccgaggga tgcgtgggcc aagggagcca gaagaacagg gaaagtcatg ccaggcagac 184800 ggaacagcaa gtgcaaaagc ccagaggcag gagagagcag gcaaagcttg agaaactgaa 184860 tctggccacc actgccgaag ctcggtgccc agtgagctgg ggagacccag gggccaggtc 184920 aggcgagcct gaaggccaag tcgggggcta agactttctc ctgaggacag tgggagccat 184980 cgagggcaca cagcacaggg agggtgtgca ccagtagact tttccaaaaa ggtccttttg 185040 gttcctataa ggggaagggg ctactggggg ctacagtgga aatggggaga caggggatcc 185100 agatgagagt tgagggcgct tggatcaggg cctgggcagt gggtgaggtg ggaggcttcc 185160 ccaggatagt ggtgtctgca cctaggactc gggtcactaa tgaggacaga gccaggcagg 185220 gcaatagagg agtgcgcatg gatgggcact tcctggccag gacagggaag aggtggagtg 185280 cagcctggag tgtgtgtccg gcagggacgt gaccgctcct gggccccaca atggacagac 185340 atgtgctcca caggtcaccc actgcccctg ggcctccatg acactgcccg gcccgtcctg 185400 ccgcgcccac ccaccatctc caacccgcct cccctcatct cctctgccaa gcaccccagc 185460 gtcctcgaga ggcaaatagg tgccatctcc caagtgagtg gtagcccttc ctttcttggg 185520 ggcttagtct tcttatctgt aaagtggggg caatgggacc aatgaagtct gagtgggggc 185580 caggctctcg ggggcctggg tcatctccac tcaggcatct ggggtctgag ctggctgggt 185640 cctgccccag gcactcaggg cctcgtccct ggggggtcac tctgtattgc agtcaagggc 185700 atggctcagg aaccaggctg tgtggcctca ggcaagttac ttaacctcct gtttccccca 185760 ctgcgaaatg gaagggcaaa tgcaaggggc tcagagggca tggccccttc acaggggagg 185820 gggccgaggc ttgggagtag cagtgacttg tctgccgtca cacagctgga cagcagcccc 185880 agcctctgac ccacacgtgg gctttttgaa caggagcgtc aggcactctg gactgtgggg 185940 gagggaccag ggtgcccctg tgaccccaca actccgcccc tacagggaat gtcggtccag 186000 ctccacgtcc cgtactcaga gcatgccaag gccccggtgg gccctgtcac catggggctg 186060 cccctgccca tggaccccaa aaagctgggt aaggctcctg gcccatccgt ctgggtggct 186120 caggctgggc tctggctgtc ctgtgggtgg ggcgggggag gaaggggtat cttggcccac 186180 ggtactccag gtagcagctg ggaggtcccc cctcagcagc cctggctgga acatggtggg 186240 gaggggcagc gcttcccagc ccctggctca ggttgggtgg ggacaagcct cccgggaccc 186300 tgctccggca gcacgtgact cgctcctctt actggtcctc agcacccttc agcggagtga 186360 agcaggagca gctgtcccca cggggccagg ctgggccacc ggagagcctg ggggtgccca 186420 cagcccagga ggcgtccgtg ctgagaggtg agggcccttc tgccctgggc ccccagcatc 186480 tgcccctgtt cctcgggtgc ccaaagggcc ctttattcaa aacctgctgg gaagtgtcat 186540 ctcccagagg gtctgggggc ccctcttcac agctgtctcc ctcaccattt aggggtaggg 186600 ggactccctc tgcgttgaaa caactagcac aacttgtggg tctctcagtc agggtggctc 186660 tcaggactgg ggcctgggga aggaagggcc acagacacgc cctcagcccc acatcttgtg 186720 tcttccaggg acagctctgg gctcagttcc gggcggaagc atcaccaaag gcattcccag 186780 cacacgggtg ccctcggaca gcgccatcac ataccgcggc tccatcaccc acgtaggtgt 186840 cctggggtgc ggcaggaagg acggttggga ccagcacggg gccagcccat cttataaccc 186900 ctcattgtca ccaaaccatt agcctcagcc gatggggtga tgactggggg acagcagttc 186960 actccatgaa ctttcatcta gtctgcatgg aatcaggcac tgggattgcc aagcacagct 187020 caaaactctg ccttcaggga gctgccatgt agtggaagga aacagaccag ggtaaataag 187080 taggctggtg aaaaccgagc aggcaggcag aatgtgagcg taccgcggct gagaatgcct 187140 ggccacggac attgcttaga caggtgagga aggtgacatg tcagctgtgg ccagaagaaa 187200 ttgagggtgc aagccatgcg ggaatctcag ggaacagcat tctaggctca gggaacagca 187260 tgtgcaaaga cagagcatga gagggttcct gaatcgtgcc aggactggtg ccccagcctt 187320 gcagctggtg agctgtggac ccaaggtttt gtgccacgtg tgtctggctc tagaacacag 187380 tgacagagcg tgggtccaca cacttgcaca cgtgcatgca tgttctaaca gtggagcttc 187440 gggcaacaag atggtccaca gggaggtgtt tttcactcag gcagcgtcaa atcccaccac 187500 agaggagcca tttacacttt gcccttctct gaaatctgca ggttttaaaa atctgagctt 187560 tcaaaggcag ctgtgctgag tgggaagggc aagtgctttg gacaaaagtc aggctgaggg 187620 ccctcgggtg ccagctccac cacctactca gacaggcagc ggcctgccct gactccgttt 187680 cccctttgct aacagtattc ctgggagagt cattctcctg aagtcgtagg gacctttgaa 187740 gttcccaggc atccacctgc tctgggttcc tgagtggcca tgacccgcgc ccttcctcga 187800 acctcccagt tacacacatc tctttgattg cttttggcag acagccagct gccaaaacat 187860 gtgagatagg caagggtcaa acttccgtgc agtctcacta ccagatagtg aggaagtcag 187920 cgtgtggcct gcacgcacag agccgtttat taactgagta ggtgccatag gcagggacca 187980 cgtggttccc agctggcaag ggaggtcaag gaagtcccag ctccctgatc ctccagggac 188040 ttcctgccca tcttgggagt agagttcatt ggggccaaga gcaagaggct acaggctcat 188100 ctcctggaag cagacgttat gcaaacagaa gcttccctgt taatgggagt ttgtccagtg 188160 tattctccca agagcagggg ccaccggctg gatttctgtt ctctgtccat gtccctgaag 188220 atggcacctc taaaatacta tagctcaaaa acatcaagct ggacacggtg gctcttgcct 188280 gtcaacccag cattttggga ggccaaggtg ggaggatagc ttgagcccag gagtttgaga 188340 ccagcctgga caaaaagagg cctgtctcta cagaaaattt aaaaattggc tgggcatggt 188400 ggcacatacc tgtagtctca gctacttggg actgggaggc aggaagatca cttgagccca 188460 ggagtttgag gctgcagtga actatgacag tgttctgcac tccagcctgg gcaatacagc 188520 aagacccctt ctcaaaaaaa aaaaatcaga tgcctcagtt tcaccatgga gagcccccct 188580 ttttaaatca tttattgtgg tgttcagtaa gccactgatt tctgcagtac aaacccagtt 188640 ctgacatgga ccatctgatg ttagggctgg atacagaaag gggtgcactt gtgttagctg 188700 cctcttgggg ggcttttccc gccaggatgc tgcaggaatc ctgtgctttc ctgatgggag 188760 aggtggctgc cccgagctgt cacctgactc agcacctatt gtgccacact gttagtgtac 188820 aggtgtctta aagcacagca gggagatgct gctcagagta tttgctttgg gaagtttggg 188880 gggagctcat cagaattcag ggcgtcttgc tgttgccctc cgcaaagacc aggatctgcg 188940 gtgaactccc cggggtacca ggtgctgccc tctgccaggg gatgtcccca gccaagcaag 189000 tccagccaga gactcagagc tcactggtcc aggtcttggg atatagtagg acctttaccg 189060 ttgaatctgc tcctggaacc ctagaaagag aagagggata ttgagatttg gggacccgtc 189120 gtctgtgcca gatgcctttg agaatcatca atgcagaagg tctccatttg tggatgtgca 189180 aactgaggct cagaaaggag gtcccacggc agcttggtag taaagttgct gtttgacacc 189240 caacattctg cttccaaagt catattctaa ctctgatgct tgtgttcttg aaagtcaccc 189300 aaggcaggat gctgccccac gtggccatct cctctctgct tgaacacatc ctccaacggg 189360 aagctcattc cctatatggc agtggttctc aattggggga aattgtgcct ccaactctct 189420 agggacattt tcgattgtcc taacttggtg ggggacacac tggggaggcg tgtactcctg 189480 gcttctagtg ctttgaagcc agggatgctg ttaacagccc acagtgcaca ggacagcccc 189540 acagcaaaga agggtccagc tccagctgtc aggagggccg aggtggaaaa cctgggttag 189600 aactaaaatt tccggtgtgc tgccctgacg tgagtccttg tcctggtttt aggaaaccaa 189660 agtgcatgac gtggtcacgg gtacagcaca ggagcagaaa ccccagcgtc cccgccagtt 189720 accgttttcg gtaactgaat gtcaaggctc tgagtagacc ccacgcagtg gtggggacac 189780 agactccagg accagaatgc ctgggttcaa gtccccgcct gccccttatt agccaggtga 189840 ccccgggtaa agtcactgtg cctccctgtg cctcggtttc cccatctgaa acaggcataa 189900 tcaatagggt tgtcttaggg ttgtttcgag gattaaatga gcaaatccat agagagcacc 189960 cagaacagcg tccactcatg ggaagcactt gacaagggat cttcattctt caggttcctc 190020 atagggtttt gttccatgca aactcttacc tatttgagac agtgtgtgtg tggacacgcg 190080 tgtgcatcgg tgggcacatg ggcttttaag cacgtctttg cctgcatttg agttgagagg 190140 ggtcctgggc tgcagcctcc tgggcgctca cccctctgca cctgcagggc acgccagctg 190200 acgtcctgta caagggcacc atcaccagga tcatcggcga ggacagcccg agtcgcttgg 190260 accgcggccg ggaggacagc ctgcccaagg gccacgtcat ctacgaaggc aagaagggcc 190320 acgtcttgtc ctatgagggt gagtcgcagg aggagaggag gcccaggacc aggggaggag 190380 tgtgcttggc ccactgaggt agcttcacag ggaggcaggg ctggattgac atcagaaagc 190440 acaatctgat aggtggtgac ctccttatcc ctgcaggtat gcaagccagc agcagggaag 190500 cgttggcctt agctgcctcc cacctctgcc cagttcttta cagtttagaa aacaaactca 190560 tggccaacct ttttagaagc ataggaggga aactgaggcc cggaacagaa gcccgagctc 190620 acgccgccag gcctccagca ccgtactgac aaaccacgca ctctctcatt ggccatgaaa 190680 gaggccatgg ccagagtgcc cctcgcccca ctgtgtccca ggctcttgct gcggagcccc 190740 catcctctcc ctctctaggc tctgggttcc agaacgagga gaccctgcca ggaaggagtt 190800 aagggaatcg agtgccggga aagagaattt cctggcagcc tagggcaccc aggggtgtgg 190860 agatgaaagc tgctaatggg cgcctctctc agcactgcag ctgcgaggcc cggaattgcc 190920 tctcctccat ccacttccgc ctgtgcccgc agccccctcc ccaggcctgg gaggtggagg 190980 tggcaccgtg tggcttagga acataatgca ctccctgctg ccacagagat agccttggag 191040 acaggcctgc agctgtgtct tgggtgccag ctcatgccct ggtgcccctg gaccgagtgc 191100 cctgggggtg gcgggaagcc tgggaagggc tggtggtggg gttagtcaag agcttgtctt 191160 gagaggtcac tgggtagagt cccaccttgg gaccccagac cagtgcctga gcctttatag 191220 gccttcagcg tatcgtcttc atcatgggtt tcagtcgggg cctttaaact ctcgtctgct 191280 ccctgggcca ggtaggcagt gcaggcagcg gcaggtgtga gactgtaggg agtggggagg 191340 actgtaggga atggggagga ctgtggtgcc tgctcacgcc gtccactccc ctgcggccac 191400 cggtcagcca ggtttctcat ctccgttttt atctgaaatc tcccgatgtt taaacatcgg 191460 cgattaattt ggaacgtttt ctgaacagca acctagtacc ctcctgttgg caacccctgg 191520 agtagctcac gggccgtggg ccacacgaag caatggttga aaagcccgag agcctgtcag 191580 ttgctcattc cctctgaggg gtggggcggg ggctcccggg gctcatttct gatagctctg 191640 gactcggctg ccctggaagg agagccctgg ctagatgggc aaagcccagc ctttaccttc 191700 gggggccacc tccgtctgtt cacctctctg cctgtccggg gagcagtgag ccgggcccat 191760 gtaggctcct ttggcctggc gaggccaccc ctgccacccc tcaccactgc ctgcaacaca 191820 cacctctccg tgcacacgca gacttgtggt cggacactca catgcacatc ggcacaggtt 191880 tctgggtgtg acacgtgtat acatacaaag ccgtgtactg cctgcaccct ggtacatgtg 191940 tgtacatgga cccacttagt tctcagcagc caggctcacg tgcatgtgcc cacatccact 192000 cctgcacaca caagacccgt gccagtgcac atgcgtgctc ctgcctgcca cacgtccaca 192060 cactgctgat gtatcggtgc acacgcgtgc tcctgcctgc ccgcacctcc actctgctgt 192120 atcggtgcac gcgtgctgct gcctgccaca catccacact ctgctgctga tgtatcggtg 192180 cacgtgtgct cctgcctgcc acacatccac acactgctga tgcgtccttg ctcacgtgca 192240 tgtgtgtgca cttgttcacg ccccatgtcg gcacccgtgg gtgtggacac agactcacgt 192300 gctcatgtgg tcacaggcac acccttgctt gcagacagag caccctggag ggctagggta 192360 cagggtgcag gcagcgtgcc ctgcatctcc caccgtgcaa ccccctggaa aagctcctgg 192420 gtcctgctgg caggccccca gggcctgcag gctgccagct ccctctggag gcctcggctg 192480 tgaggctttg tgacggggcc agcatggaag cactgctggc tcctgcctac cggctctgcc 192540 tgtcctgcct gcccaccgtg gtcctgggcc cgtgcccagc tcctcaccga gtgctttgtg 192600 tggtttccag gtggcatgtc tgtgacccag tgctccaagg aggacggcag aagcagctca 192660 ggaccccccc atgagacggc cgcccccaag cgcacctatg acatgatgga gggccgcgtg 192720 ggcagagcca tctcctcagc cagcatcgaa ggtgatagca gggaggagac ttcatctctc 192780 ggtgccccct ggtgggcggt ggggggatgg ctgaccccgt tttacagatg gggaaaccga 192840 ggctgggctt tctgaggctc catctggagg tagcgcaggg accttcccgt gctgggtcct 192900 actccaccat catcgtgggg atgaccactg gcggctgtaa acactgaccc ctgtcactgc 192960 ccagtgtcgg ctcagggagc cacggaatga tggcctcacc ctctcctacc caggtctcat 193020 gggccgtgcc atcccgccgg agcgacacag cccccaccac ctcaaagagc agcaccacat 193080 ccgcgggtcc atcacacaag gtactgccct gttccctgct ccctcgttgc ccccaacggg 193140 tgtacagtca cgcagggcgc gggagggaga gacacagcca gagtgtggtg ggaactcagg 193200 acaagtatgc agaaaggcct gcagcacaca tgtacatgat cagtacgtga gctacggagc 193260 aagggtgtct cttacttatt tcaaaacaaa aacaaaaagc aaaataccac cgatcacccc 193320 tgtgctttta ggtgtcacat agcaactgtc ctgtgcttgg cactaaccca ggtgccacct 193380 gcgtatcgtt ttacagaaca tcctggtgag gcacatgcga ttgggagagg cttggagagc 193440 tccgagaact ctttcaggtt ctcgcggctg gtccatggca cagccagcta ctgtgaactt 193500 ggcagctttg tgggttttat tttttatttt tttattttgt tgttgttgtt gctgtttgag 193560 acagggtctc attctgttgc ccaggctgga gtgcagtggc acgatctcag ctcactgcag 193620 cctccgcctt tcaggcttaa acaatcctcc cacttcagcc tcccaagtag ctgggaccac 193680 agatgcacac caccacatct agctaatttt tgtatttttg tagaggtggg gtttcaccat 193740 gttgcccagg ctggtctcga actcctgagc tcaagctgtc tgcctgccgc agccccccag 193800 agtgttggga ttacaggcgt gagctactgc acccagcctg tggttttagc ttcatgattt 193860 catagtgttc ccgacttgct gaggtggttc agttaatatt cttgttttat gtgtgaagaa 193920 gctgaggccc agagaggtca gatttcctgg tcaaggtcac acagcaagtg gggatttgaa 193980 ctcaggcaga ctagctccag aacccactgg tgtggaggct cttgatgggt ctgggtgggg 194040 cggggcgtga gggtcagtgc tgtcggcccg gcagggatcc ctcggtccta cgtggaggca 194100 caggaggact acctgcgtcg ggaggccaag ctcctaaagc gggagggcac gcctccgccc 194160 ccaccgccct cacgggacct gaccgaggcc tacaagacgc aggccctggg ccccctgaag 194220 ctgaagccgg cccatgaggg cctggtggcc acggtgaagg aggcgggccg ctccatccat 194280 gagatcccgc gcgaggagct gcggcacacg cccgagctgc ccctggcccc gcggccgctc 194340 aaggagggct ccatcacgca ggtatggccc agggccaggc acacgggccc agttctagga 194400 ggggtggcgg tggctgtggg gcactgccct gggcctctcc acatggggaa accgaggctg 194460 agagccctcg cgtaccttac agtcacccag ctgctcatca ccgggcctca gctgtgcgtg 194520 ttccagggct gcgcaggggg caccaggctc ctgacctgat tctactgaac tcacattgtt 194580 cccattcttc agggagggaa actgagtccc agagaggcca ggcaggcttc caaggccaca 194640 ggactaaaca tagtgacgag taactgcctc cgttgaatct ttgtgagggt ccaggtgcgg 194700 cctgaggatg ttgcatgcgt tcattgtttc accccctagc aatgctctga ggtcgttttc 194760 ttaatgacct tattttattg ctgagtaaat tgaggttcag agaggttcaa cgactcaccc 194820 agagtcacgc agcaaatgca gttgtgaaac ccaaattcag atgttcctac agccgcagca 194880 tccactgcac ccaccagcag gttgcaccac aagaggcccc agtcccccca ggcggcccca 194940 gctcagtagg ggaagttccg tgccgatggt acgaggacga ggagctgttc ggtggaaagc 195000 ccctgaaggc cactgtcctt ccacatgggc agaggtggcc tcttgtgaag gggaaggaga 195060 atgggagcca ccacggggct gtggggctgt gaggcggaag gactggggtg ggtgtcccgg 195120 gaggggttcc agcttgtagg aaggttttga agccagggag aaggcagaag cagtaagatc 195180 cctgattgcc aggggaaggg tttggctctc agcccctagg caattatgga gtccttggaa 195240 gcatccaccg catgaccaag acagggtcca gattctagaa tattcttttg aaaaacaagg 195300 gcagttcccc ttcttacgac agtaatgaag acatccctaa atagagtttt gttgcttgca 195360 aagccctaaa gtcccaccat atcaagtgtc tccgaagcct gctgaaaaga ggcaggggac 195420 ctggtggcct ggctacgaag gtcccagtct ggactgtgac ccccccattt cctcaccatc 195480 ctttctgtct ggagggcaaa cacctcagcc ctgacctcag tgtccctggg gctgaaagcc 195540 tcagggcggg tagtattggg tctgggtgct gactttttct gcttggcatt gggtgggcca 195600 tggagggtcc caggctgaac agaggaatgt tttttaccca catgagggtg ttgggcttct 195660 ttctcgcaaa ctccagggac catcagagag cccaccactc gcggcaggga gagttgactg 195720 ttgaactttt tacccctttc tgcagtcccc ccagggagcg tggggaccag ggtcaggccc 195780 agggtgcgca gggcagtaag taacaagtgt gccatctcag ggttagcaaa gccctctgtc 195840 tccctgcctc tggaggcatc agatgtcact tccatcttat agatgacaaa ctttttgagg 195900 ctcagaaggg ggatgcagct ggtctgggct atggctgtgg ccagggctag agcttacatc 195960 ccctctgccc cagggcaccc cgctcaagta cgacaccggc gcgtccacca ctggctccaa 196020 aaagcacgac gtacgctccc tcatcggcag ccccggccgg acgttcccac ccgtgcaccc 196080 gctggatgtg atggccgacg cccgggcact ggaacgtgcc tgctacgagg agagcctgaa 196140 gagccggcca gggaccgcca gcagctcggg gggctccatt gcgcgcggcg ccccggtcat 196200 tgtgcctgag ctgggtaagc cgcggcagag ccccctgacc tatgaggacc acggggcacc 196260 ctttgccggc cacctcccac gaggttcgcc cgtgaccacg cgggagccca cgccgcgcct 196320 gcaggagggt gagtggggtg tgcatgggcg tgagtggggt gggcgcctgt ctggagaagc 196380 tgtgcctccc catccaccat tagcttagtt tgcacctggg atatcctcgc cacccgcttt 196440 ccaccacatc caaaccacct gcaggcccgt gggctctgcc tccgattcca aaccctgtcc 196500 aactccttgc cacctcccag accaccgtgg tgtctcacct agcttccccc acgcccctcc 196560 ctcttcctgc tgtaatccac tctgcaaaca gctacccgga tactttctaa aaatgcaaat 196620 catattattc cacttccctg cttccatcct tctagcaact tcacacattt tgctatggcc 196680 ttggggcgcc tgcctgttgg ggccctgcct gcctctcatt cagccggatt ccttcgtcct 196740 ccccagcccc agcccctggg ccctctttct ctttgttccc tggccatgct tagctcggtc 196800 aattcagtat ttgctggggg cctttgcgtg gctcctcctc tctgcctgcc atgtccccgc 196860 cttccagatc tttacttagt gggtttcttt ccatccctca ggtctttgtt tacatattac 196920 atccttgggg aggcttctaa ccagaccccc tatctccagt tcatatcaca tgctgtgaca 196980 ttttaaaatt gtcttccggc caggcatggt ggctcacacc tgtaatccca gcagtttggg 197040 aggtcaaggc aggcagatca cctgaggtca ggagttcaag accagcctgg tcaacatggt 197100 gaaaccctgt ctctactaaa aatacaaaaa aataaccggg tgtggtggta cgcacctgta 197160 ttcccagcta ctcgggaggc tgaggcagga gaatcacttg agcctgggag gcagaggtta 197220 cagtgaacgg agatcgtgcc attgcactcc agcctgggca acaagagtga aactcttatc 197280 tcaaaaaaaa aaaaaaatga aagaaaattt tcttctgagc gtgtttcact ctgtaattct 197340 catttgtttg ctagtttatc acctgtctct cgcattgaat gtcagcttgt gagggctggg 197400 atttctgttt cgttcactgg ggtgacccca gttctcacaa caatgcttgc cacgtagtag 197460 aggctgcatc aatatttttt aattgattga gtgagtgaat ggatgaaaga atgaattttt 197520 taaaaactat aacacaaaag caaatgagtc agtgagcaaa aagtgaacta aggcaatgaa 197580 gaaatgaagg agtgaatgaa gagacctggt ccttgggatc ccgaggtccc tatcctcaaa 197640 caactccccg taaatgccag ccccagaggc ccgatgcatc caccttgccc gtccacaggc 197700 agcctttcgt ccagcaaggc atcccaggac cgaaagctga cgtcgacgcc tcgtgagatc 197760 gccaagtccc cgcacagcac cgtgcccgag caccacccac accccatctc gccctatgag 197820 cacctgcttc ggggcgtgag tggcgtggac ctgtatcgca gccacatccc cctggccttc 197880 gaccccacct ccataccccg cggcatccct ctggacgcag gtgattgccc tggggctccc 197940 agaaccctgc agtggtgctg aacagggcca cggacctcat cagtgttcgc tcagggactc 198000 cttaggcatc aactgtcagg ttcccctgga tggcgaaact gaggcctcgg gattggaaga 198060 cccaacagtg taatcatgag cttaggttgg agcagaattt ctcttagtag tttgcaggac 198120 atgtggggtt aaacatttca gtggttttct tttccggcag gacttatcag tgcctttagc 198180 aatgcaaagg tatagaatga ggacttgagt atatgcattt ttcaaataga catgatctga 198240 aagtcttttt taaaagttgc cgggcacggt ggctcacacc tgtaatccca gcactttggg 198300 aggccgaggc aggcggatca caaggtcagg agatagagac catcctggct aacacggtga 198360 aaccccgtcc ctactaaaaa tacaaaaact agccgggtgt ggtggcgggc gcctgtagtc 198420 ccagctactc gggaggctga ggcaggagaa tggcgtgaac ccgggaggcg gagcttgcag 198480 tgagccaaga tcgcgccact gcactccagc ctgggcgaca gagcgagact ccttctctaa 198540 aaataaaaga aattaaaaaa aaagaaataa aaaaagttgc atccctttgg agtgttaatc 198600 tgcattggga tgtcctatgt ttgggacaac tttgatgcaa aaagcatcct tcgtagaagt 198660 caccctcttg tgtcctggcg tgatgttttc ctgctgtccg acgctcagtt ctggtttgtg 198720 ctttgggcag ccacacatgt aggtgggaga agctgtccgg gtgcagaagt agggggcatc 198780 cagacaggtg gagcgacacc atcaggccta ggtatggctg gcctcacatg agctcccctc 198840 tgccccgcag ccgctgccta ctacctgccc cgacacctgg cccccaaccc cacctacccg 198900 cacctgtacc caccctacct catccgcggc taccccgaca cggcggcgct ggagaaccgg 198960 cagaccatca tcaatgacta catcacctcg cagcagatgc accacaacgc ggccaccgcc 199020 atggcccagc gagctgatat gctgaggggc ctctcgcccc gcgagtcctc gctggcactc 199080 aactacgctg cgggtccccg aggtgagtgg gtgggcagac cacctccgct gggtttggcc 199140 ttattcccaa aggacatggg cgtgcccctg tggcctcgcg gaggcagcta gacctggtca 199200 ccttgtgggt caccttgtgt gaacggacct gagtgggtgg cctggggttg tgcgtgctgt 199260 gggtgctggt tggcatctgg taggtgagtg cacagcgtgt ggctcctggc tgcatcctca 199320 gtgggtgtgc gtgcatctgt gtatactctt aggatacagg ggcctcagga gtttaaagat 199380 caaaatgtgg ccgggcacag tggctcatgc ctgtaatccc agcacttggg gagggcgagg 199440 caggtggata acaaggtcag aagttcgaga ccagtctgac caacatggtg aaacccgtct 199500 ctcctaaaaa tacaaaaatt agccaggcat ggtgatgcgc acctgtagtc ccagctactc 199560 actaggctga ggcaagagaa tcacttgaac ccaggaggtg gaggttacag tgagtggaga 199620 ttttaccatt gcactccagc ctgggcaaca gggcaagact gtgtctcgaa aaaaaaaaaa 199680 agatgaaaat gtgaggctgt ttggagtttg ttcctttgcc ttgtaaacag cccacagctg 199740 ctttgcgtgc acacgttcca gggccatcct cagaaatgct tctggaataa ccaagttcta 199800 gctggggctc agctggaaaa gctgaagtca cacttaagta ttttgaacag tgaggattga 199860 atacagggaa tggattgtgt aggcgtcaga ggctgaaggg gcacagaggg cctgagatgg 199920 gaaccagtga gggcagctgc aggagatgcc ccggctcggg cttgggagca gaagaggagg 199980 tggtaccgag agaacctgag cattcagaaa agggttccat ggctggtgct gggagccgag 200040 gagggagtgc ctgccaccag ctctgctggc tccaggagtg tgtgccgtgc tctccaggag 200100 ggtgatctgg ccggtgggca gcctggcctc tctcctccct gtggctacag ccctggccca 200160 acacctcccg caggcatcat cgacctgtcc caagtgccac acctgcctgt gctcgtgccc 200220 ccgacaccag gcaccccagc caccgccatg gaccgccttg cctacctccc caccgcgccc 200280 cagcccttca gcagccgcca cagcagctcc ccactctccc caggtagcgc cactgcccag 200340 tctggggtgg ggaccccggc atccatggga ggcggctggg ggatgggcgg gcagaagccc 200400 tgctctcttt cccaccccag aagacaaagc caggctcttc ttcggccctg gggctgagtc 200460 tctggccttt gggtttccta ggaggtccaa cacacttgac aaaaccaacc accacgtcct 200520 cgtccgagcg ggagcgagac cgggatcgag agcgggaccg ggatcgggag cgggaaaagt 200580 ccatcctcac gtccaccacg acggtggagc acgcacccat ctggagacct ggtagggcat 200640 cagagccccc accccccgct ccgggactcc ttgtgggccg caagaggcct ccccctgctg 200700 atgccactga ctgtcaccag gtacagagca gagcagcggc agcagcggcg ggggtggggg 200760 cagcagcagc cgccccgcct cccactccca tgcccaccag cactcgccca tctcccctcg 200820 gacccaggat gccctccagc agagacccag tgtgcttcac aacacaggca tgaagggtat 200880 catcaccgct gtggagccca gcacgcccac ggtcctgagg tgggccaggt tggcatgggg 200940 gagggggcgg gcaggtggat gggtggtcag taggaggatg agcagataag aggatgcttg 201000 gtgggaggta tatgggaggt gggtgggtgg gcagatgtgt gggggtagaa gaatagacta 201060 tgtgtgagta gtggatgggt gggtggtcgg gttaggtggg tgtgtgggtc agtgggaagt 201120 taggttagct gcgtgggtgg atggatggat ggatgggggg gtggtcgggt taggtgggtg 201180 ggtgggtcag tggaaagata gatggctggg ttagctggtt ggatgggtgg atgatcaggt 201240 ttggtaggta ggtgggtggg tggaaggata gatggccggg ttagccagat aggtggttgg 201300 gttaggtggg taggtgggtc agtgggagga tagatggtta ggttagctgg gtgggtggat 201360 ggatggatgg gtgggtgata gggttaggta ggtaggtggg tgggtgagag gatagatagc 201420 tgggttagct gggtggatgg atgggtgggt ggtcacgtta ggtaggtaag tagatgggca 201480 aaaggataga tggccaagtt agctaaatag ggtgggtggg tggtaggtag gtaggtaggt 201540 agtgggtagg taaaaacccc tnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 201600 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 201660 naaacacttt gctgaatcca gaaacactga tgcaagaggt gggtttccat ggccttagga 201720 agctccacct ctgtggcttt gcagagtaca gccccctcct gcctgctttc atgggctggc 201780 attgagtgtc tgccactttt ccaggcacat ggtgcaagct gtcaatggag ctaccattct 201840 ggggtttgga gaacaatggc cctcttctca cagcttcact agtccctaac tggggactct 201900 gtttgggggc tctgactcta catttccctt ctgcactgcc ctaacaaagg ttctccatga 201960 gggctctgcc cctgcagcaa acttctgcct ggatatcctg gcatttccat acatccactg 202020 atatctaggc tgaggattca aatccacaac tcttatgctc tgtgcatctg caggcttaac 202080 accacatgaa agccactaag tcttatggct gacaccctat cgagcagtgg gttaacatat 202140 atctggagcc cttttagcta caactggcac ttgagtggct gggacacagg gagcaatgtc 202200 ccatggatgt gcagggcagc aggtccctgg gcatggacaa tgaaaccatt cttctctcca 202260 agacctctgg gcttgtgatg ggaggggctg ctacaaagtt ctctgaaata ctttcaaggc 202320 attttcccac attgtcttgg ctattaacat tcagcaatgt tacatatgca aatttctgta 202380 gatggcttga attactccca taaaatgggg tattcttttc tagtgcatgg acagactgca 202440 aatattctaa acttttatgc cctgcttccc ctttaaatat aactctcagt ttcagacatc 202500 tcattgctca cacatatgac catatgctgt tagaagcatc caggcgacat cttcaatgct 202560 ttgctgctca gtgtgtgggg gtgtactaca atacattcat gcttatatac aatgcatttg 202620 aggttgaggc atgtaaaaat actaaggcac tgtgtgtatg ttgtttgtgc atgatactgt 202680 aactccttgt ctctgaaaac agtacaagga acaggatgtg tgataaggag tgctgaagac 202740 agcatcctaa gaatgtggtt gatgcttcag atgaataaat aagtccatat gacctcatgc 202800 ctgcccccaa atagccacct gttgatgaat tataatctnn nnnnnnnnnn nnnnnnnnnn 202860 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 202920 nnnnnnnnnn nnnnnnnngt tagtgcttcc ttcaggatct cttgtacggc aggcctgttg 202980 gtctcttatc atttgcttgt ctgtaaagga ttttatttct cctttgctta tgaagtttag 203040 tttagctgga tgtgaaattc tgagtagaaa attattttct ttaagaatct taaatattgc 203100 cccccactgt tttctgactc atagggtttc tgcagagaga tccgctgtta gtctgatgag 203160 cttcccttgt gggtaacctg acctttctct ctggctgctc ttaacctttt ttcctttatt 203220 tcaactttgg tgaatctgat gattatgtgt cttgggttac ccttctctag gagtgtcttt 203280 gtggtgttct ctgtatttcc cgaatttgaa ttttggcctg tcttgctagg ttggggaagt 203340 tctcctggat aatatcctga agagtgtttt ccaacttgct tccattctcc ccatcacttt 203400 tcaggtacac caagcaaatg tagatttggt cttttcacat agtcccatat ttcttggagg 203460 ctttgttctt tccttttcat tcttttttct ctaatcttgt tttcacattt tatttcatta 203520 atttgatctt cagtcgctga tatcctttct tccacttgat tgatttggct attgacactt 203580 gtgtatactt cacgaagttc tcatgctgtg tttttcagct ctatcaagtc atttattctc 203640 tactccaaac tggttattct agttagcaat ttatttaatc ttttttcaag gttcttagct 203700 tccttgcatt gggttagaac atgctccttt agctcagagg agtttgttat tacccacctt 203760 ctgaagccta cttctgtcaa ttcatcaaac tcattctcca tccagttttg ttcccttgct 203820 ggcgaggagt tgtgatccta tgaaggagaa gagacattct ggttttggga attttcagtc 203880 tttttgcact ggtttctccc catcttcatg gatttatcta cctttggtct ttgatgttgg 203940 tgacctttgg atggggtctc tgagtggaca tccttctgtt gatgttgatg ttattccttt 204000 ctgtttgtta gttttccttc taacagtctg gcccctctgc tgcaggtttg ctgcagtttg 204060 ctggaggtcc actccagact ctgtttgcct gggtatcact agcggaggct gcagaacaac 204120 aaagattgct gcctgttcct tcctctgcaa gcttcttccc agagggacac ccaccagctg 204180 ccagccggag ctcttttgta tgaggtgtct gttggccccc actgggaggt gtctcccagt 204240 caggcaatgt ggggtcagga cccgcttgga ggaggcagtc tgtgatgaac tattctcann 204300 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 204360 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnct ccctcctcag cctccagagt 204420 agctggacta cagtgtgcac cacaatgacc agccaatttc cttgatattt ttttaagaga 204480 tgggatctta ctacgtggta caggcctcag cctcccaagt agctgggatt ataggtaaga 204540 gccaccacac ccagcccaaa ttagattgtt tctaaagaga tattctgacc acgcctttaa 204600 atatctaatc ataagtcacc tactgaaaaa ccgtccttga cttctgtatt agtttcctat 204660 tgctgctgta acacaaactt agtggcttaa aatggcacaa atgtattgtc tgacaattct 204720 ggaggtgaga atctagaatg tgtctcactg ggctaaaacc aagatgccag gctgcgttct 204780 cttctgaatg cctagcggga aattcattgt cttgcctttt accacttcct tggagaagga 204840 gtctacatgc tttttttggc gcatggccct cttctgtatt caaagctagc aatggctggt 204900 tggatctttc tcaaactcta tcactctgac ctgcctctgt cttctacttt taagtacctt 204960 gtgattccat tgggattgtc tggataactc aggatagtct ccttatttta acatcaactg 205020 tttaacaaca ttaactcgct ctttaactct ggtttctctt tgctatgtga cataagacac 205080 ttacagtttt tgagggttag gatgtggaca tcgtggaagg gagacattat tcctcctacc 205140 atggcttccc agtatctagc aaacccatcc tggctgcctg ggtcttctac actgtgggct 205200 cgaatttact ctccagcctt acccccaaga cctcatgtcg tatgtgccct cgagttccac 205260 acacaccagt ccatccagat cccccaacac accccacact cacacagctc atagcattgt 205320 ttcttgcatt ttatcttctt tgatgttctc ttcattccac gctgcctccc tttactcacc 205380 accaagatga aactctgttc atcctcggac ttatagcaaa tgcatctttc tccatgaagc 205440 tttcccccta actttttccc tctggatgtt catatcataa tgtttgtacc tctctgtann 205500 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 205560 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnntt tgatttgtgg gttggtggtg 205620 gcgttaagta ggtaggtaag tgggaggaag aaagaatggc ccagattagc caatgtgaag 205680 gaaaggatgg gggggtggnt aagttaggaa ggtagggggg tgggggagag tatagacgct 205740 ggcttagntg ggggggtgga tgggtgggtg gtagggttag ggaggtagnt gggtgggtga 205800 gagtatagat ggctgggtta gctgggtggg tgggtggatg ggtgggtggt agggttaggt 205860 ggatgatgga atggatggtt ggatgagtaa ttgtggggat gagtggatgg aggccccagt 205920 ggatggacga tgagttgggc ggtgggatga gtagatgggg aggttgtttg gtttgagaat 205980 agaatctgtg gagagggaga gactgaatgg ggactgtgag gaaagacttt cccggtcccc 206040 cacatttagc aaggccagca aggaaaagag gtgtccctct tgcctggaca aagtcccaag 206100 tttctctgag atgggagagg cccctgagtg ccctctggtg acacacactc cagagactgt 206160 gggcagagct gcttcaccag gggggtgggg tcacacctca acacccttcc ctgcccggaa 206220 cctttttttt tttttttttt tgatggagtt gtactctgtc gcccaggctg gagtgcagtg 206280 gtacgatctc tgcttactgc aacctccacc tcctgggttc aagtgattct cctgcctcag 206340 cctcccaagt agctgcagtt acaggcacgt gcaaccacac ccggctaatt tttatatttt 206400 tagtagaaat gcggtttcac cacgttggcc aggctggtct caaacttctg acctcaagtg 206460 atctgcctgc ctcagcctcc caaagtgccg ggattacagg cgtgcgccac cgcactcagc 206520 ctccaggacc tatttagagg caacttactc ctccaaaatg aattttcatt caaaaaagta 206580 cttgtgcccc aacttgccgc ttggatgcct gaagtcatac ctcccctaat cattatttca 206640 attatgaaaa atggcatcgt ttcccaaaag cagtggcgac tttgtcaccc ctgactcaga 206700 cccagcaggt gcatgaagca ctaatccctg gctgtgggga gcagggttcc gcacacaggc 206760 tctgtgggat atgcccgtga cagccgattc aaaaatataa tggagaaaac gagtgcctgc 206820 ccactgcccg ctcatgaatg aggctctggg aggtagagtt agcgagagat gggggtgccc 206880 ccatggaaac gcagggctcc gggaaggcca cgtgggtgga gcagccggct cctgttccag 206940 ccccagccct gtgcaggggc agctgtgccc cagcttctca ctcacagagc tgggaacagc 207000 agctttctct gttctcaacg cccaccctgg ccgccccctg gcatccttcc ccttgctctc 207060 tcactcctca cgtggctttt ttagctcttc gggtatcctg agcaggccca gctccctcat 207120 gtgccccctc cctgaagacc tcctagccct gcctcagctt ccttgccgtt ctctcctggt 207180 acctcattga ctacctccac acagttacca ggctctgtag agcttgggat atctgttaat 207240 gtgatcgtag tctgttttct gaattagatg gtaagatgct tgcatccgtt ttatgaccgc 207300 tgtattcaca gtgtctagaa cagtgcctgg cacctagtag ctgcttaatc agaagttttg 207360 gaatgatgca aggaatgaat gaacgaatga gtgggatggg tcaaaccatg acgcacagag 207420 tctggcaggt tacagtcagg agggcagttt cactctggga gcagcagggg atgtggattt 207480 atcccagggc aatggggact catcgagggt ggtggaggaa gagggcagct cccatgactg 207540 cctgaccgcc ttctctcctc ccccaggtcc acctccacct cctcacccgt tcgcccggct 207600 gccacattcc cacctgccac ccactgccca ctgggcggca ccctcgatgg ggtctaccct 207660 accctcatgg agcccgtctt gctgcccaag gaggcccccc gggtcgcccg gccagagcgg 207720 ccccgagcag acaccggcca tgccttcctc gccaagcccc cagcccgctc cgggctggag 207780 cccgcctcct cccccagcaa gggctcggag ccccggcccc tagtgcctcc tgtctctggc 207840 cacgccacca tcgcccgcac ccctgcgaag aacctcgcac ctcaccacgc cagcccggac 207900 ccgccggcgc cacctgcctc ggcctcggac ccgcaccggg aaaagactca aagtaaaccc 207960 ttttccatcc aggaactgga actccgttct ctgggtaaga ccaccctgac agcggccacc 208020 ttcatagacg cgattatcat gcgtcaaatt gctcacgata aaggggcgcg agaaggaggt 208080 gcgctggcca acggctcccc tcgcgatggt aagacttccg gcccgcaccc accccgtctc 208140 gtggtccaaa gatattttca gatctctgct ttttactttg gcccccgttt tttttgttgt 208200 tggttttggt attttgtttt gaagcccatc cgtcctcgcc ggtttgcacg cgctgacgac 208260 tactccggcc gcgcctgccc ctctggtttg ggggcgctca tcatttgcac atcattttac 208320 catggttttt tttttttgga tttttgcttt tttttcttta atgaatggat ctgtgattct 208380 gacttcgact gcgcccccat ctccctcttt gcgcctgtgt ccagggagca gggatggggc 208440 tgcgggaggg ctcgggccta cgcccccacc tgccggctgc ctggatgctg tcggactggg 208500 ggaagtggag gcaggcggtg caaggagaag ctgaggcggg gcagggacct gcgctgtcga 208560 ggaggagctg ggtctggctc ttgcatcttg ccctgtcccc agcccctgta ccccagaaaa 208620 aggggagccc tctgcctctg gacccctgcc ttggccctag ttcatggctc ctctctgttg 208680 gactgggatg gccgaggcta tagcccaggc ggggccccgg ggacccaggg tcactcccag 208740 ccacaccccc acttctcact ccgccccaca cactccttcc ccagagaccc atgctgcccc 208800 catctcacgc tggcctcgcc cggcctccac cacctgaacc catctctgtc ccttcttgcc 208860 taatctctct ctgtgtctcc ctctctgtct gtctctgtcc cgggctctgc atctctctcc 208920 acctctccct tggcctccct gtctctcccc aacacccctc tctgccttac tgtctttggg 208980 agcccaaacc ctacccctag cttgggttcc ccttgacccc cccggggtcc cagccagctg 209040 ggagggcagc cctgcccctc gggctccgaa accctgggcc cggtgcctga ctctgcaccc 209100 cccgcctgcc ctaggttacc acggcagcag ctacagcccc gaaggggtgg agcccgtcag 209160 ccctgtgagc tcacccagtc tgacccacga caaggggctc cccaagcacc tggaagagct 209220 cgacaagagc cacctggagg gggagctgcg gcccaagcag ccaggtacgc cccacccagt 209280 acccaggccc ccgaagccct gcacagtgag gaccctcaag gccccatcat gcagatagga 209340 aaacagaggt gcctaaaggc caaggaattg gctggatcat gaggctcaaa ggcatggggc 209400 tgggatttgg gcccagcagc cctggggcca gcagacaccc cctgaccagc tctgctctgc 209460 ctgcaggccc cgtgaagctt ggcggggagg ccgcccacct cccacacctg cggccgctgc 209520 ctgagagcca gccctcgtcc agcccgctgc tccagaccgc cccaggggtc aaaggtcacc 209580 agcgggtggt caccctggcc cagcacatca gtgtaactac gcgttctctg ctgctgcttg 209640 tcacctttgc acctgggggc accaggcctg gagaggggat ggggaacccc acagcccttc 209700 tgtcctggcg gggtggctgg gggatccagg gcatggcgct ggggggatcc agggcgtggg 209760 tgagggtgag atcccaaagc cccgagcacc ggcaccatca ccgcccccta atccatggga 209820 ggagcctgtg atgcgagccg atggcatctt cacgggcaat gaggccttcc tggtggccca 209880 ggtttctcag tgtcatgggc tggtctcatc agccatctgc caactaccag cttgggaccg 209940 ctgaccacag ccccactccc atgcacactg ggacacggag gcccagaggg tggcgggcag 210000 gtccacagtc acccaggaag ctggccccac ccaggattct gccccgagct ccgtctagcc 210060 cctccccacc cccagaaggt tctgtcagga gagtgctgcc tgactctggg cccccccact 210120 tgcctgcagg aggtcatcac acaggactac acccggcacc acccacagca gctcagcgca 210180 cccctgcccg cccccctcta ctccttccct ggggccagct gccccgtcct ggacctccgc 210240 cgcccaccca gtgacctcta cctcccgccc ccggaccatg gtgccccggc ccgtggctcc 210300 ccccacagcg aagggggcaa gaggtgagcg agggatgggg gtgcctcttg ctggtcagcc 210360 ggcgggaggc cttcgtcagc tgcctgcctc agagctgggt ctgagctcag ctgcatatga 210420 ggcccgcctg gtgccattgc acaggcaaga aatggaggct ccaggagatg ggggagtcac 210480 agagcggata cataacgaat aatagctgat gaaagtacat gctgtgctca gtgggttcca 210540 ggcactcacg tgtacccttt acacacagcc ccccaggaga cataggcagc attctcccca 210600 tttcacagat gaagaaacta aggcctggag aagtgaattc acttgcccac aggggcacag 210660 tcagtaggtg acagaggggg atttgttcca gggctgtatg attagagagc agcctttcca 210720 cacatgcaca cccacacaca tgcgcacaca cacacatgca cacccgcaca catgcgcacc 210780 cgcacacaca cacgtgcaca cccacacaca tgcgcgcgca cacacatgca cacccgcaca 210840 catgcgcgcg cacacacaca tgcacacccg cacacatgcg cacacacaca tgcacacccg 210900 cacacaggcg cacccgcaca cccctgtaga cacaggcaca tgcacatgct cacgcacact 210960 cccactccca cccccgcccc cacccccacc ctggtgaacc gtggggcctc tgggggtcaa 211020 aagagaaaga gaggggaggg ccctgagctc cagggtgaag gaggcgtttt ggtgggggcg 211080 gggggggtaa tgtgtgtgcg aggacagaca tggcaagaca gcaggacatc tttggggggc 211140 agtggtgtag ctggcactgg ggtacaacca gaattcagag caggggtcaa taaactgtgg 211200 cccatgggcc agatctagcc cgggccctct gtttgtacaa ttcatgaact aaaaaaatga 211260 ttttacattt ttaaagggtt gtttaaaaaa aaaataaaaa tgataacgat acatgccaga 211320 gattacttgt ggtcgaaaat gcctaaaacg tttatgattt ggccacgtac aggaaaagcg 211380 tgtggggccc tggtttagag tggagggagg gtgcgccccc tcagtaggga gacctctgac 211440 cacatctggg gccctttctc catccaggtc tccagagcca aacaagacgt cggtcttggg 211500 tggtggtgag gacggtattg aacctgtgtc cccaccggag ggcatgacgg agccagggca 211560 ctcccggagt gctgtgtacc cgctgctgta ccgggatggg gaacagacgg agcccaggta 211620 cttctgtggg cacatgcgct gcccccggga tgctctggta tcccttgccc atccttggcc 211680 ccagtccacc gtggtgccat gtggagagtg acaagggcac agggctcagc tgggtgacct 211740 caagcctgcc aagcaggttt caccaacttg ggggtgtgat acatgcccac cctccctggg 211800 gagacctcag tggtagcttt ccatgctttg ggctgggatc tcagctggac caggcccccg 211860 ttgacagccc ctgttgaacc tctaagaaat aatgagctag gtgtgctggg ccagaccggg 211920 ggcgatgggt gaggtgggac ctgagaagga agctgggccc gctgcccctg gggaagggca 211980 tgatcggaac ccaatttcag tccttggggc tctcttgaga gggtcaggct ggagcaagtg 212040 gtcagaggca gcccaccacg cagccaggcg tctcccaaga cacccctagc cccaggacgg 212100 gtgaaccgca gaggagattt caggagccgt gatcttctac caggcagggg atgcaggcgt 212160 gggggcgggt gaagcttgct tccaaatgtc taaggcatct caggtggtga gttccccatc 212220 atcaaaggca tgcaagctcg gcaccaagtg agctgatgtg aggtgtttga tcctcacagc 212280 aggatgggct ccaagtctcc aggcaacacc agccagccgc cagccttctt cagcaagctg 212340 accgagagca actccgccat ggtcaagtcc aagaagcaag agatcaacaa gaagctgaac 212400 acccacaacc ggaatgagcc tgaatacagt aaggggcctg caggctcccg gggaagcatg 212460 gggccacagg tgggcgggtg gcctgcctgg gcagctggag ccgcccagtg gcagaaaccc 212520 acggtgcacc ttcgaaagct aagtggccct gctgaccacc tccccccagg ccctttgcct 212580 cacatttggg gagccccagg gcagtttctt gatttgctgg gctttccata ggagcttact 212640 ggcacagaag aatagcaccc agcacatagt aggtgcccag tgaatacctg catgaatact 212700 gggaccaggg gttggatccc tcccacacaa gggccgggcg cctcccacac tcagcacctg 212760 tgtggctttg cacccattga cgtggttgct gggtatgaac gccccactct gcttcccagt 212820 ccctagcaca gcgcctggca gttagcagat ccaccaggga atacgtgagt gggtgggcaa 212880 ataaagaatc tgtcacagtc cccgacccca agaagcctca tctgccaggg aagtttggac 212940 aaatcacaga tgcttttccc ttcctggggc tggagtagaa accttgcaga tagtcactgg 213000 cttgccgggc acggtggctc atgcctatag gcccagcact ttgggaggat gaggcaggag 213060 gattgcttga agccaggagt tcgagaccag tctgtgcaac atagcaagac cccatctcta 213120 caaaaaactt taaaaacagg cacacaccta tagtccaagc tactggggag gctgagatag 213180 gaggatttct tgagcctcgg aggtcaaggc tgcagtgagc tatgatcaca ccactgcact 213240 ccagcctgga caacagagca agacactgtc ttaaaaaaaa aaaaaatctc tgacccaggc 213300 tggtaactcc agggccctgt aagtgcagtc cagggaaccg tagcatcagc atccccaggg 213360 tactggttag aaatgcaggc ccttggccag gcgcggtggc ttacgcctgt aatcccagca 213420 ctttgggagg tcaaggcggg tggatcatat gaggtcagga gtttgagacc agcctgacca 213480 acatggtgaa accccgtctc tactaaaaat acaaaaatta gccaggcgtg gtggcggatg 213540 tctgtaaccc cagctactcg ggaggctgag gcaggagaat cacttgaacc tgggaggcgg 213600 aggttgcagg gagccgagat tgcacaactg cactccagcc tgggcaacag agcgagactc 213660 tatctcaaaa aaaaaaaaaa aaagaaatgc agacgcttgg ccctgtccca ggcctgctgc 213720 atgagaacct gcaatgcaca agtttcccca ggtgatgcca gcacacctgg cctggaccac 213780 acgggactgg tagggcaggt aattcccaga gacctggggg cctcacccac tctgtcaccc 213840 gcttccagat atcagccagc ctgggacgga gatcttcaat atgcccgcca tcaccggaac 213900 aggtaaccca tccagccctt gctatatggc tgccctggtc ccctccgctc cctccccacc 213960 cctgctccag ctgtcatgaa gggacgagga gccttcgcta gtctgggtgt accccctcat 214020 tctgggatga actaaccgca cagtaggatt cagagtcaca caacaggcag gcgaggcttg 214080 ttccctgtgt agacaggatc ctcgctgtgc agggaatctc tggagttaag atcccctcgg 214140 gtggttagta agtatcagat gcaccctcac cagctggaaa ctcaccttgc ttcttcgcca 214200 gcctcagctg gagatgcaca tgtctggacg aggggtgggc ctgagctcag agcacaagcc 214260 tccgagttca ctcgggcgtt tgttatagct agagcttcat tccttaaatc cagccaggga 214320 actgggaagc cttacttttt ctttcaagat caaatacagg tgtgtggcag agataggtgt 214380 aaaattgaca cgcactttta agctgaaact taagacttct atgatctttt ggacttaggg 214440 gtcccttgag gttggagccc catcctctag gagggcccca ttgtgtattt ccttggtgag 214500 tctggggtgt ggcctctggg ggtcactctg catgggcagg cctggcccag tggggctgag 214560 gcagttttgg ggtcggctgc ctctgtgtgg gtgcctggtt atcctctggt cctttggtgg 214620 aagctgaggc caggatggag gtcggagagg tttgctgatc ttccctgggg aacattcctg 214680 ggccttgagc cctgggaatg gtgagcgaag gatagtcgtt cagatattat cagggggtca 214740 gcgaggcctc caaatgggag tcccaactag gacacctcca cctgcccagt gactagacac 214800 cgggggcatt gccaagcctc aggcaacggg aagaagacaa tttggtcgaa acaacaagag 214860 ggttagaaat gaatgttcct gggatgttct aaatcttgaa gtaggtgcta gacacacagg 214920 tgtatctgtg tgtaaaaact catggcatgg tacagtgaag atttatgcta acacttatat 214980 ataaatattt tgtatttatc tttttaagac acggtctttc tgtcacctag gccagagtgc 215040 agtggtgcaa tcacagctca ctgcagcctc cgcctcccag gcttagatga tcctcctacc 215100 tctcagcctc ctgagcagct gggactacag gcatgcgcca ctgcacccga gtaatttttt 215160 atcttttttg tagagacagg ctctcaatat gttacccagg ctagtcttga actcctgtcc 215220 tcaagctgag gatcctccca cctcgactga tttttgtttt ttgtgtttgt ttgtttgtct 215280 gtttgtttga cagagtcttg ctctgtcgcc caggctggag tgcagtggtg caatcttggc 215340 tcactgcagc ctctgcctcc cgggtttcag cagttcttcc acctcagcct cccaagtagc 215400 gggattacag acacccgcca ctacacctgg ctaatttttg tatttttagt agagacgggg 215460 tttcatcata ttggccaggc tgatctcgaa ctcctgacgt cagatgatcc acccacattg 215520 ggcctcccaa agtgctggga ttacaggcgt gagcagtcac gcccagcctg attttttctt 215580 tttatgcagt tttagtccac aagaagaaat tttccaggct ccagtctttg ccactcaacc 215640 tgtgtcagac ttcaccttta taaatggaga tcgttaagcc tggagccagc tccatcaggt 215700 cacggactcg tggccttggg tagaaggccc agtcgcgctg ctgtgatttc agcactcacc 215760 cttgttggaa atgttgcttt ttcttcatgc acatggctgt tttttcaaaa gtgctgcaga 215820 aatgtggcca agacagcaga aaaggtgtga gcatccctgg ctacaaacgt atttgaaacc 215880 aaaagggaaa agaaaacgca ggcagccagc agttgctaca gaaacgtgat tttcaaagca 215940 tctgcatcac ccgcaacctc atggaagcct cggtttggtt tacaaaggag cgagtggtcg 216000 gaaagacgat ttgaccactt tgtattcgta tgattcattc ggagcagaag tttaaaactc 216060 catgaaacac ttgccccgtg gtgggcacgg tggaatgggg cttcactggg ggcttttgaa 216120 agcaaaggct ggtttaacaa aagttctgaa aagacagcac ctctgggggg tgtgcaaagg 216180 cccccacctc cacgtggttc acaagaaaga aaaaagggaa aggaaatgtg gttaacagaa 216240 aaggaggttt ccccgattgt caggaggtgt tctggaagca tcctcttggg accggtttgt 216300 tgattcgacc actttgtcct tgggactggg cagctgggcc agctggggcc ggaccagggc 216360 tggtcccgtg attgtgtcta cttctgccct gtcccctgca cgcaccgtaa ctgcatggct 216420 atgaccccgc cctcagcgtc cgtctctgca cctctttctc ctcatggctc ctgggtgggg 216480 agaggcagag ggaggagagc aggcccagct tggtggggag gtacggggct gcacgtccca 216540 tcacacaggt ggaggtgggg cagcgggagg accatctggt caccttctct ctctcagtcc 216600 cttccccagc ccccagccag cccccagctc tggcttgagc caattttcta gcagcctgtt 216660 ccccaaacag ggtagccctc ccatctccca ccctctccat taaggccact tgagatttaa 216720 aaaaaaaaca aacaaaacag ccccagctag gattggaggt gcagacgggg cttgtgattt 216780 cccagaggac agaataggaa tgagaatagg ggctggtggg ggcatctgac ctcccctacc 216840 ccacctccct ggcagtgccc aagagcttcc ggggccccag gtagaaggaa ccagcctctc 216900 cccttttatc accacccagc aggaaaaaaa gggtggggag ggatagggaa ataaatatgt 216960 tgctttgccg aaatgtgctc actgtgtatt tctctctcct cctcctcctc ctcctccttc 217020 cctctctctc tcccttctct ctctctgtcg cccctctggc tccccctccc cggcccccat 217080 gtgtctgtct gtctgtctgt ctctctctcc caggccttat gacctataga agccaggcgg 217140 tgcaggaaca tgccagcacc aacatggggc tggaggccat aattagaaag gcactcatgg 217200 gtaaatatga ccagtgggaa gagtccccgc cgctcagcgc caatgctttt aaccctctga 217260 atgccagtgc cagcctgccc gctgctatgc ccataaccgc tgctgacgga cggagtgacc 217320 acacactcac ctcgccaggt ctgcaggcca cccccgcccc gcccccgtct gtccccaccc 217380 ccggtgtgat taatcctcgc tcctccgcgc tcctctgaca accccctcct cgagctttgg 217440 agcttgtgac tttatttttg tgcgtgtttg acctcgttct ggagtttgct aatctgaagc 217500 tgggctgaca ccccccaagt gtctgtaccc tctgcccccc agccccggcc ctcctgccca 217560 ctaggcccga agcgctgccg cctccctcgg acactcacac tgctgtccgc cccccagtcc 217620 tcccgccttc ctccctgcgg ggacccggct tcttggccca tctgtctcct tgggggagag 217680 caggctggag tgaagcccca cccacactgt gtggacaggg gaatggcagc caggcctgtg 217740 ctcagcatct gccaggccca ctatgtgtcc tcagctgccc cttagcctgg tggggaggag 217800 cccagggtct gtctcagccc tgggagtcag ggagccttag gggtcagcct ggttccccat 217860 caataccctc tgtatcgggg cagggagctg aggagagagt tgcagttgtc caacctggac 217920 actgaggccc caagaagctt ctggagcctc tgtgggggtc aggcctggcc tcaggggtcc 217980 tgacttctct gcacggggcc tggatcctgc ctagccttag catggtcctg gggccacgct 218040 caaactggaa gcccagcttc atgcttaggg ttccagcccc tggggctggg gtcgctgcag 218100 gacagcccag ggggctattg caaacagcag acagtttagc cacctccccc tgcccagcag 218160 aaactatctc caccctccag gctcatggct ggccatctgg tcaaccctgg cttcccagct 218220 ggggcgggca gcagggagga ggggttcacg ttactgctct ccctccctct ttggagggcc 218280 catggcagga cctcaccctg cccctgtggc cccaccgtag cgtcggtgct gtcttcactg 218340 cccaacgcag ccccttccca tcttgtcccc ctgcaggtgg cggcgggaag gccaaggtct 218400 ctggcagacc cagcagccga aaagccaagt ccccggcccc gggcctggca tctggggacc 218460 ggccaccctc tgtctcctca gtgcactcgg agggagactg caaccgccgg acgccgctca 218520 ccaaccgcgt gtgggaggac aggccctcgt ccgcaggtgg gcaccaggtg gggacagggc 218580 tgggctcgct gagcccccaa cactgggctg tgaatgctgc cggggcactg aatgctgagc 218640 gcctgctgca tgcagagctc agactcgggc ctgttctgtg gaaacgctgt ccaggggcct 218700 gggcagctga gcctggctca cgaaccatca ggatgcttct gccaggggca caggcagagg 218760 aaaagggtgt ggttggggcc ggccagatca catgggcctg gtggaccatc caggggagcc 218820 tggacttcct ttgatgggta gtgaggaggc gtggagggct ttcggaaggg aaatgctcat 218880 ctaacatagg gtcagaaggc ccctgggaga atagaccaga gggacggtga ataggctact 218940 gctatagtcc aggcaaaaga cagcggcagg gtgtgaacag ggacggaagt agaacaggtg 219000 aagagaggca gacggttctg agacctgttc gcaattagaa aggtctggga ggactgttgg 219060 acagaaacgc tgaggcctct gttcccggtg tggtgggcag gcggccagca ggggctgccg 219120 ggctcacaga ggcctcctgg gcatctttcg cttcttcccg caggttccac gccattcccc 219180 tacaaccccc tgatcatgcg gctgcaggcg ggtgtcatgg cttccccacc cccaccgggc 219240 ctccccgcgg gcagcgggcc cctcgctggc ccccaccacg cctgggacga ggagcccaag 219300 ccactgctct gctcgcagta cgagacactc tccgacagcg agtgactcag aacagggcgg 219360 gggggggggc ggtgtcaggt cccagcgagc cacaggaacg gccctgcagg agcagggcgg 219420 ctgccgactc ccccaaccaa ggaaggagcc cctgagtccg cctgcgcctc catccatctg 219480 tccgtccaga gccggcatcc ttgcctgtct aaagccttaa ctaagactcc cgccccgggc 219540 tggccctgtg cagaccttac tcaggggatg tttacctggt gctcgggaag ggaggggaag 219600 gggccgggga gggggcacgg caggcgtgtg gcagccacac gcaggcggcc agggcggcca 219660 gggacccaaa gcaggatgac cacgcacctc cacgccactg cctcccccga atgcatttgg 219720 aaccaaagtc taaactgagc tcgcagcccc cgcgccctcc ctccgcctcc catcccgctt 219780 agcgctctgg acagatggac gcaggccctg tccagccccc agtgcgctcg ttccggtccc 219840 cacagactgc cccagccaac gagattgctg gaaaccaagt caggccaggt gggcggacaa 219900 aagggccagg tgcggcctgg ggggaacgga tgctccgagg actggactgt ttttttcaca 219960 catcgttgcc gcagcggtgg gaaggaaagg cagatgtaaa tgatgtgttg gtttacaggg 220020 tatatttttg ataccttcaa tgaattaatt cagatgtttt acgcaaggaa ggacttaccc 220080 agtattactg ctgctgtgct tttgatctct gcttaccgtt caagaggcgt gtgcaggccg 220140 acagtcggtg accccatcac tcgcaggacc aagggggcgg ggactgctgg ctcacgcccc 220200 gctgtgtcct ccctccctcc cttccttggg cagaatgaat tcgatgcgta ttctgtggcc 220260 gccatctgcg cagggtggtg gtattctgtc atttacacac gtcgttctaa ttaaaaagcg 220320 aattatactc cagttacaaa ggtttcttct ctacctcaga ctgggcagcc aatagggcag 220380 gcgtttaggg gacagtggga gtatacccct ggagggccaa ggccacatcc gcctgagtca 220440 ccagggagtg gatccttttg caagttgaat atttataccc ttggtaagga catcaccatg 220500 aggacatcaa atagtcacat ctgtggtgaa ggtctcaagt gttcacaccc atggtaagag 220560 tgtgtcagat gttcacatgg gttcacaccc atgtgtcagg tattcacatg atggtcaggg 220620 tgtcatgttc acactcatgg tgagagggtg tcaggtattc acacccatgt atcaggtatt 220680 cacaccatgc tgagggtgtc aagtagtcac acccatggta agagtgtcag atgttcatac 220740 tcatggtgtt aggtattcac accatggcga gggtgtcaga tgttcacaca tggtgtcagg 220800 tgttcacacc atggtgaggg tgtcatgttc acactcatgg tgtcaggtat tcacaccata 220860 gtgagggtgt cagatgttca cacatggtga gagggtgcca ggtattcatt cccatgtgtc 220920 aggtgttcac accgtggtga gggtgtcaag tggtcacacc atggtgagag ggtgtcagat 220980 gttcacaccc atgtgtcagg 221000 13 2930 DNA H. sapiens CDS (456)...(2765) 13 tttgttagtt tgtctgtttg cacttaaagt tctaagcact ttggaaagtt tctaagcaac 60 ttctcacttc caagcaacaa cttaaccaac actaacaact tactattatt aattagtatt 120 ttcttggctc acccccgcac agcaccgtgc ccgagcacca cccacacccc atctcgccct 180 atgagcacct gcttcggggc gtgagtggcg tggacctgta tcgcagccac atccccctgg 240 ccttcgaccc cacctccata ccccgcggca tccctctgga cgcagccgct gcctactacc 300 tgccccgaca cctggccccc aaccccacct acccgcacct gtacccaccc tacctcatcc 360 gcggctaccc cgacacggcg gcgctggaga accggcagac catcatcaat gactacatca 420 cctcgcagca gatgcaccac aacgcggcca ccgcc atg gcc cag cga gct gat 473 Met Ala Gln Arg Ala Asp 1 5 atg ctg agg ggc ctc tcg ccc cgc gag tcc tcg ctg gca ctc aac tac 521 Met Leu Arg Gly Leu Ser Pro Arg Glu Ser Ser Leu Ala Leu Asn Tyr 10 15 20 gct gcg ggt ccc cga ggc atc atc gac ctg tcc caa gtg cca cac ctg 569 Ala Ala Gly Pro Arg Gly Ile Ile Asp Leu Ser Gln Val Pro His Leu 25 30 35 cct gtg ctc gtg ccc ccg aca cca ggc acc cca gcc acc gcc atg gac 617 Pro Val Leu Val Pro Pro Thr Pro Gly Thr Pro Ala Thr Ala Met Asp 40 45 50 cgc ctt gcc tac ctc ccc acc gcg ccc cag ccc ttc agc agc cgc cac 665 Arg Leu Ala Tyr Leu Pro Thr Ala Pro Gln Pro Phe Ser Ser Arg His 55 60 65 70 agc agc tcc cca ctc tcc cca gga ggt cca aca cac ttg aca aaa cca 713 Ser Ser Ser Pro Leu Ser Pro Gly Gly Pro Thr His Leu Thr Lys Pro 75 80 85 acc acc acg tcc tcg tcc gag cgg gag cga gac cgg gat cga gag cgg 761 Thr Thr Thr Ser Ser Ser Glu Arg Glu Arg Asp Arg Asp Arg Glu Arg 90 95 100 gac cgg gat cgg gag cgg gaa aag tcc atc ctc acg tcc acc acg acg 809 Asp Arg Asp Arg Glu Arg Glu Lys Ser Ile Leu Thr Ser Thr Thr Thr 105 110 115 gtg gag cac gca ccc atc tgg aga cct ggt aca gag cag agc agc ggc 857 Val Glu His Ala Pro Ile Trp Arg Pro Gly Thr Glu Gln Ser Ser Gly 120 125 130 agc agc ggc agc agc ggc ggg ggt ggg ggc agc agc agc cgc ccc gcc 905 Ser Ser Gly Ser Ser Gly Gly Gly Gly Gly Ser Ser Ser Arg Pro Ala 135 140 145 150 tcc cac tcc cat gcc cac cag cac tcg ccc atc tcc cct cgg acc cag 953 Ser His Ser His Ala His Gln His Ser Pro Ile Ser Pro Arg Thr Gln 155 160 165 gat gcc ctc cag cag aga ccc agt gtg ctt cac aac aca ggc atg aag 1001 Asp Ala Leu Gln Gln Arg Pro Ser Val Leu His Asn Thr Gly Met Lys 170 175 180 ggt atc atc acc gct gtg gag ccc agc acg ccc acg gtc ctg agg tcc 1049 Gly Ile Ile Thr Ala Val Glu Pro Ser Thr Pro Thr Val Leu Arg Ser 185 190 195 acc tcc acc tcc tca ccc gtt cgc cca gct gcc aca ttc cca cct gcc 1097 Thr Ser Thr Ser Ser Pro Val Arg Pro Ala Ala Thr Phe Pro Pro Ala 200 205 210 acc cac tgc cca ctg ggc ggc acc ctc gat ggg gtc tac cct acc ctc 1145 Thr His Cys Pro Leu Gly Gly Thr Leu Asp Gly Val Tyr Pro Thr Leu 215 220 225 230 atg gag ccc gtc ttg ctg ccc aag gag gcc ccc cgg gtc gcc cgg cca 1193 Met Glu Pro Val Leu Leu Pro Lys Glu Ala Pro Arg Val Ala Arg Pro 235 240 245 gag cgg ccc cga gca gac acc ggc cat gcc ttc ctc gcc aag ccc cca 1241 Glu Arg Pro Arg Ala Asp Thr Gly His Ala Phe Leu Ala Lys Pro Pro 250 255 260 gcc cgc tcc ggg ctg gag ccc gcc tcc tcc ccc agc aag ggc tcg gag 1289 Ala Arg Ser Gly Leu Glu Pro Ala Ser Ser Pro Ser Lys Gly Ser Glu 265 270 275 ccc cgg ccc cta gtg cct cct gtc tct ggc cac gcc acc atc gcc cgc 1337 Pro Arg Pro Leu Val Pro Pro Val Ser Gly His Ala Thr Ile Ala Arg 280 285 290 acc cct gcg aag aac ctc gca cct cac cac gcc agc ccg gac ccg ccg 1385 Thr Pro Ala Lys Asn Leu Ala Pro His His Ala Ser Pro Asp Pro Pro 295 300 305 310 gcg cca cct gcc tcg gcc tcg gac ccg cac cgg gaa aag act caa agt 1433 Ala Pro Pro Ala Ser Ala Ser Asp Pro His Arg Glu Lys Thr Gln Ser 315 320 325 aaa ccc ttt tcc atc cag gaa ctg gaa ctc cgt tct ctg ggt tac cac 1481 Lys Pro Phe Ser Ile Gln Glu Leu Glu Leu Arg Ser Leu Gly Tyr His 330 335 340 ggc agc agc tac agc ccc gaa ggg gtg gag ccc gtc agc cct gtg agc 1529 Gly Ser Ser Tyr Ser Pro Glu Gly Val Glu Pro Val Ser Pro Val Ser 345 350 355 tca ccc agt ctg acc cac gac aag ggg ctc ccc aag cac ctg gaa gag 1577 Ser Pro Ser Leu Thr His Asp Lys Gly Leu Pro Lys His Leu Glu Glu 360 365 370 ctc gac aag agc cac ctg gag ggg gag ctg cgg ccc aag cag cca ggc 1625 Leu Asp Lys Ser His Leu Glu Gly Glu Leu Arg Pro Lys Gln Pro Gly 375 380 385 390 ccc gtg aag ctt ggc ggg gag gcc gcc cac ctc cca cac ctg cgg ccg 1673 Pro Val Lys Leu Gly Gly Glu Ala Ala His Leu Pro His Leu Arg Pro 395 400 405 ctg cct gag agc cag ccc tcg tcc agc ccg ctg ctc cag acc gcc cca 1721 Leu Pro Glu Ser Gln Pro Ser Ser Ser Pro Leu Leu Gln Thr Ala Pro 410 415 420 ggg gtc aaa ggt cac cag cgg gtg gtc acc ctg gcc cag cac atc agt 1769 Gly Val Lys Gly His Gln Arg Val Val Thr Leu Ala Gln His Ile Ser 425 430 435 gag gtc atc aca cag gac tac acc cgg cac cac cca cag cag ctc agc 1817 Glu Val Ile Thr Gln Asp Tyr Thr Arg His His Pro Gln Gln Leu Ser 440 445 450 gca ccc ctg ccc gcc ccc ctc tac tcc ttc cct ggg gcc agc tgc ccc 1865 Ala Pro Leu Pro Ala Pro Leu Tyr Ser Phe Pro Gly Ala Ser Cys Pro 455 460 465 470 gtc ctg gac ctc cgc cgc cca ccc agt gac ctc tac ctc ccg ccc ccg 1913 Val Leu Asp Leu Arg Arg Pro Pro Ser Asp Leu Tyr Leu Pro Pro Pro 475 480 485 gac cat ggt gcc ccg gcc cgt ggc tcc ccc cac agc gaa ggg ggc aag 1961 Asp His Gly Ala Pro Ala Arg Gly Ser Pro His Ser Glu Gly Gly Lys 490 495 500 agg tct cca gag cca aac aag acg tcg gtc ttg ggt ggt ggt gag gac 2009 Arg Ser Pro Glu Pro Asn Lys Thr Ser Val Leu Gly Gly Gly Glu Asp 505 510 515 ggt att gaa cct gtg tcc cca ccg gag ggc atg acg gag cca ggg cac 2057 Gly Ile Glu Pro Val Ser Pro Pro Glu Gly Met Thr Glu Pro Gly His 520 525 530 tcc cgg agt gct gtg tac ccg ctg ctg tac cgg gat ggg gaa cag acg 2105 Ser Arg Ser Ala Val Tyr Pro Leu Leu Tyr Arg Asp Gly Glu Gln Thr 535 540 545 550 gag ccc agc agg atg ggc tcc aag tct cca ggc aac acc agc cag ccg 2153 Glu Pro Ser Arg Met Gly Ser Lys Ser Pro Gly Asn Thr Ser Gln Pro 555 560 565 cca gcc ttc ttc agc aag ctg acc gag agc aac tcc gcc atg gtc aag 2201 Pro Ala Phe Phe Ser Lys Leu Thr Glu Ser Asn Ser Ala Met Val Lys 570 575 580 tcc aag aag caa gag atc aac aag aag ctg aac acc cac aac cgg aat 2249 Ser Lys Lys Gln Glu Ile Asn Lys Lys Leu Asn Thr His Asn Arg Asn 585 590 595 gag cct gaa tac aat atc agc cag cct ggg acg gag atc ttc aat atg 2297 Glu Pro Glu Tyr Asn Ile Ser Gln Pro Gly Thr Glu Ile Phe Asn Met 600 605 610 ccc gcc atc acc gga aca ggc ctt atg acc tat aga agc cag gcg gtg 2345 Pro Ala Ile Thr Gly Thr Gly Leu Met Thr Tyr Arg Ser Gln Ala Val 615 620 625 630 cag gaa cat gcc agc acc aac atg ggg ctg gag gcc ata att aga aag 2393 Gln Glu His Ala Ser Thr Asn Met Gly Leu Glu Ala Ile Ile Arg Lys 635 640 645 gca ctc atg ggt ggc ggc ggg aag gcc aag gtc tct ggc aga ccc agc 2441 Ala Leu Met Gly Gly Gly Gly Lys Ala Lys Val Ser Gly Arg Pro Ser 650 655 660 agc cga aaa gcc aag tcc ccg gcc ccg ggc ctg gca tct ggg gac cgg 2489 Ser Arg Lys Ala Lys Ser Pro Ala Pro Gly Leu Ala Ser Gly Asp Arg 665 670 675 cca ccc tct gtc tcc tca gtg cac tcg gag gga gac tgc aac cgc cgg 2537 Pro Pro Ser Val Ser Ser Val His Ser Glu Gly Asp Cys Asn Arg Arg 680 685 690 acg ccg ctc acc aac cgc gtg tgg gag gac agg ccc tcg tcc gca ggt 2585 Thr Pro Leu Thr Asn Arg Val Trp Glu Asp Arg Pro Ser Ser Ala Gly 695 700 705 710 tcc acg cca ttc ccc tac aac ccc ctg atc atg cgg ctg cag gcg ggt 2633 Ser Thr Pro Phe Pro Tyr Asn Pro Leu Ile Met Arg Leu Gln Ala Gly 715 720 725 gtc atg gct tcc cca ccc cca ccg ggc ctc ccc gcg ggc agc ggg ccc 2681 Val Met Ala Ser Pro Pro Pro Pro Gly Leu Pro Ala Gly Ser Gly Pro 730 735 740 ctc gct ggc gcc cac cac gcc tgg gac gag gag ccc aag cca ctg ctc 2729 Leu Ala Gly Ala His His Ala Trp Asp Glu Glu Pro Lys Pro Leu Leu 745 750 755 tgc tcg cag tac gag aca ctc tcc gac agc gag tga ctcagaacag 2775 Cys Ser Gln Tyr Glu Thr Leu Ser Asp Ser Glu 760 765 ggcggggggg gcggggggcg gtgtcaggtc ccagcgagcc acaggaacgg ccctgcagga 2835 gcagggcggc tgccgactcc cccaaccaag gaaggagccc ctgagtccgc ctgcgcctcc 2895 atccatctgt ccgtccagag ccggcatcct tgcct 2930 14 20 DNA Artificial Sequence Antisense Oligonucleotide 14 agtcctcgtc atcagctcac 20 15 20 DNA Artificial Sequence Antisense Oligonucleotide 15 ctcttggcag tggtggccct 20 16 20 DNA Artificial Sequence Antisense Oligonucleotide 16 atgttcctgc accgcctggc 20 17 20 DNA Artificial Sequence Antisense Oligonucleotide 17 ctccagcgag gctgtgtcct 20 18 20 DNA Artificial Sequence Antisense Oligonucleotide 18 tcactggcac cagaaactgc 20 19 20 DNA Artificial Sequence Antisense Oligonucleotide 19 tggagcccga catggtggtg 20 20 20 DNA Artificial Sequence Antisense Oligonucleotide 20 ccgtggcggc accagctcca 20 21 20 DNA Artificial Sequence Antisense Oligonucleotide 21 gctggcccac cctctgcatg 20 22 20 DNA Artificial Sequence Antisense Oligonucleotide 22 gctgttggca gttttgcggc 20 23 20 DNA Artificial Sequence Antisense Oligonucleotide 23 ttgacagtgg cttcagcctc 20 24 20 DNA Artificial Sequence Antisense Oligonucleotide 24 aggcttctct gcctccttgt 20 25 20 DNA Artificial Sequence Antisense Oligonucleotide 25 tgtgctggga atgcctttgg 20 26 20 DNA Artificial Sequence Antisense Oligonucleotide 26 ctccttgggc agcaagacgg 20 27 20 DNA Artificial Sequence Antisense Oligonucleotide 27 gccgccacct ggcgaggtga 20 28 20 DNA Artificial Sequence Antisense Oligonucleotide 28 tgttctgagt cactcgctgt 20 29 20 DNA Artificial Sequence Antisense Oligonucleotide 29 catcatttac atctgccttt 20 30 20 DNA Artificial Sequence Antisense Oligonucleotide 30 ggcccaccct gctctgcatg 20 31 20 DNA Artificial Sequence Antisense Oligonucleotide 31 gcatgtaagg cttcagcctc 20 32 20 DNA Artificial Sequence Antisense Oligonucleotide 32 ctcattccca gaggcatgta 20 33 20 DNA Artificial Sequence Antisense Oligonucleotide 33 ttgacagtgg ctgggccact 20 34 20 DNA Artificial Sequence Antisense Oligonucleotide 34 gctgcgaagg cctccttgtc 20 35 20 DNA Artificial Sequence Antisense Oligonucleotide 35 atgaacctac cagaaactgc 20 36 20 DNA Artificial Sequence Antisense Oligonucleotide 36 accagacaag gctctgggct 20 37 20 DNA Artificial Sequence Antisense Oligonucleotide 37 tcactggcac ctgcgggaaa 20 38 20 DNA Artificial Sequence Antisense Oligonucleotide 38 acccccttac cgtgtgcgtc 20 39 20 DNA Artificial Sequence Antisense Oligonucleotide 39 cccagtgtcc tgaattccta 20 40 20 DNA Artificial Sequence Antisense Oligonucleotide 40 cagccttctt ctgcagggtg 20 41 20 DNA Artificial Sequence Antisense Oligonucleotide 41 cgctggccca ccctgctggg 20 42 20 DNA Artificial Sequence Antisense Oligonucleotide 42 gaccgagttc agccccaggc 20 43 20 DNA Artificial Sequence Antisense Oligonucleotide 43 gcatgtaagg ctggaaggaa 20 44 20 DNA Artificial Sequence Antisense Oligonucleotide 44 acattcgtac ctgggccact 20 45 20 DNA Artificial Sequence Antisense Oligonucleotide 45 ggcttctctg ctgagggcag 20 46 20 DNA Artificial Sequence Antisense Oligonucleotide 46 gctgcgaagg ctgggaagaa 20 47 20 DNA Artificial Sequence Antisense Oligonucleotide 47 cacttgttac ttactgccct 20 48 20 DNA Artificial Sequence Antisense Oligonucleotide 48 tcatatttac ccatgagtgc 20 49 20 DNA Artificial Sequence Antisense Oligonucleotide 49 ggcctgcaga cctggcgagg 20 50 20 DNA Artificial Sequence Antisense Oligonucleotide 50 gccgccaccc atgagtgcct 20 51 20 DNA H. sapiens 51 agggccacca ctgccaagag 20 52 20 DNA H. sapiens 52 gccaggcggt gcaggaacat 20 53 20 DNA H. sapiens 53 aggacacagc ctcgctggag 20 54 20 DNA H. sapiens 54 tggagctggt gccgccacgg 20 55 20 DNA H. sapiens 55 catgcagagg gtgggccagc 20 56 20 DNA H. sapiens 56 acaaggaggc agagaagcct 20 57 20 DNA H. sapiens 57 ccaaaggcat tcccagcaca 20 58 20 DNA H. sapiens 58 ccgtcttgct gcccaaggag 20 59 20 DNA H. sapiens 59 tcacctcgcc aggtggcggc 20 60 20 DNA H. sapiens 60 acagcgagtg actcagaaca 20 61 20 DNA H. sapiens 61 catgcagagc agggtgggcc 20 62 20 DNA H. sapiens 62 tacatgcctc tgggaatgag 20 63 20 DNA H. sapiens 63 gacaaggagg ccttcgcagc 20 64 20 DNA H. sapiens 64 taggaattca ggacactggg 20 65 20 DNA H. sapiens 65 cccagcaggg tgggccagcg 20 66 20 DNA H. sapiens 66 ttccttccag ccttacatgc 20 67 20 DNA H. sapiens 67 agtggcccag gtacgaatgt 20 68 20 DNA H. sapiens 68 ctgccctcag cagagaagcc 20 69 20 DNA H. sapiens 69 ttcttcccag ccttcgcagc 20 70 20 DNA H. sapiens 70 agggcagtaa gtaacaagtg 20 71 20 DNA H. sapiens 71 gcactcatgg gtaaatatga 20 72 20 DNA H. sapiens 72 cctcgccagg tctgcaggcc 20 73 20 DNA H. sapiens 73 aggcactcat gggtggcggc 20 

What is claimed is:
 1. A compound 8 to 80 nucleobases in length targeted to a nucleic acid molecule encoding SMRT, wherein said compound specifically hybridizes with said nucleic acid molecule encoding SMRT and inhibits the expression of SMRT.
 2. The compound of claim 1 which is an antisense oligonucleotide.
 3. The compound of claim 2 wherein the antisense oligonucleotide comprises at least one modified internucleoside linkage.
 4. The compound of claim 3 wherein the modified internucleoside linkage is a phosphorothioate linkage.
 5. The compound of claim 2 wherein the antisense oligonucleotide comprises at least one modified sugar moiety.
 6. The compound of claim 5 wherein the modified sugar moiety is a 2′-O-methoxyethyl sugar moiety.
 7. The compound of claim 2 wherein the antisense oligonucleotide comprises at least one modified nucleobase.
 8. The compound of claim 7 wherein the modified nucleobase is a 5-methylcytosine.
 9. The compound of claim 2 wherein the antisense oligonucleotide is a chimeric oligonucleotide.
 10. A compound 8 to 80 nucleobases in length which specifically hybridizes with at least an 8-nucleobase portion of a preferred target region on a nucleic acid molecule encoding SMRT.
 11. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
 12. The composition of claim 11 further comprising a colloidal dispersion system.
 13. The composition of claim 11 wherein the compound is an antisense oligonucleotide.
 14. A method of inhibiting the expression of SMRT in cells or tissues comprising contacting said cells or tissues with the compound of claim 1 so that expression of SMRT is inhibited.
 15. A method of treating an animal having a disease or condition associated with SMRT comprising administering to said animal a therapeutically or prophylactically effective amount of the compound of claim 1 so that expression of SMRT is inhibited.
 16. The method of claim 15 wherein the disease or condition is an inflammatory disorder.
 17. The method of claim 16 wherein the inflammatory disorder is rheumatoid arthritis.
 18. The method of claim 15 wherein the disease or condition is a hyperproliferative disorder.
 19. The method of claim 18 wherein the hyperproliferative disorder is cancer.
 20. The method of claim 19 wherein the cancer is selected from the group consisting of leukemia and breast cancer. 